A potassium channel modulator, its preparation method, pharmaceutical composition and application

Abstract

The present application provides a kind of potassium channel regulator, its preparation method, pharmaceutical composition and application. Specifically provided are compounds as shown in formula V or pharmaceutically acceptable salts thereof. The potassium channel regulator compound of the present application has one or more of the following effect advantages: (1) novel structure; (2) good KCNQ2 / 3 channel opening activity; (3) weak KCNQ4, KCNQ5 opening activity, high KCNQ2 / 3 selectivity; (4) good in vivo efficacy, good protection effect on seizures; (5) low neuro-motor toxicity; (6) high brain-blood ratio; (7) high plasma, brain tissue concentration.

Description

Potassium channel modulators, methods of making, pharmaceutical compositions, and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024111048544, filed on August 12, 2024, and Chinese Patent Application No. 2025110956965, filed on August 5, 2025. This application incorporates the entirety of the above-mentioned Chinese patent applications by reference. TECHNICAL FIELD

[0002] The present application provides a potassium channel modulator, a method of making, pharmaceutical compositions, and uses thereof. BACKGROUND

[0003] Kv7.1-Kv7.5 channels are a class of important voltage-gated potassium ion channels, whose encoding genes are KCNQ1-KCNQ5. Among them, KCNQ2 / 3 potassium ion channels play an important role in regulating neuronal excitability and are the basis of neuronal M current. Changes in the channel opening activity of KCNQ2 / 3 can affect the membrane potential of cells, and in turn affect the excitability threshold of neurons. Studies have shown that KCNQ2 / 3 mutations can cause benign familial neonatal convulsions (BFNC) and other epilepsy-related diseases. In addition, one of the pathophysiological characteristics of pain is the excessive excitation of neurons, and the activation of KCNQ2 / 3 channels can reduce the electrical excitability of neurons, therefore, KCNQ2 / 3 has important application value in the treatment of pain, especially neuropathic and inflammatory pain. KCNQ1 is mainly expressed in myocardium, and compounds that affect the opening of KCNQ1 ion channels may increase the risk of cardiac side effects. KCNQ4 / 5 are expressed not only in the nervous system but also in various smooth muscle cells, and they control the contractility of smooth muscle cells, affecting KCNQ4 / 5 channel activity, which may cause balance disorders, urinary retention, and other risks. Therefore, highly selective KCNQ2 / 3 modulators are beneficial to reduce side effects and improve drug tolerance.

[0004] KCNQ2 / 3 selective channel openers have been widely studied in recent years as innovative drugs for the treatment of epilepsy and pain, and have become a clear drug target for the treatment of epilepsy. Retigabine (RTG) is the only KCNQ2 / 3 channel opener approved for marketing in the European Union and the United States. Its clinical efficacy is significant, but due to its weak KCNQ2 / 3 potassium channel opening activity, the clinical dosage reaches 1.2 grams per day, and some patients will experience adverse reactions such as pigmentation and urinary retention after long-term use, which limits its clinical application. Other KCNQ2 / 3 potassium channel openers under research, such as HN37 and XEN-1101, are currently in the clinical stage. These compounds have significantly improved activity compared to RTG, but the types are limited and there is still room for improvement. SUMMARY

[0005] The present application provides a KCNQ2 / 3 potassium channel modulator with a novel structure, in particular provides a compound as shown in formula V or a pharmaceutically acceptable salt thereof,

[0006] wherein,

[0007] n is 0, 1, 2 or 3;

[0008] m is 0, 1, 2, 3, 4, 5 or 6;

[0009] each R 1 is independently D, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl or C1-C6 alkyl substituted with one or more R 1-1 ; each R

[0010] each R 1A is independently D, -OH, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl or C1-C6 alkyl substituted with one or more R 1-1 ; each R

[0011] each R 1-1 is independently D or halogen;

[0012] R 2 is methyl or methyl substituted with 1-3 D;

[0013] R' is H or D;

[0014] R 3 is C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more R 3-1 ; C1-C6 alkyl substituted with one or more R 3-2 ; -Si(C1-C6 alkyl)3 or C1-C6 alkyl substituted with one or more R

[0015] Each R 3-1 Each is independently D, halogen, or C1-C6 alkyl;

[0016] Each R 3-2 Each is independently either D or halogen;

[0017] X and Z are independently represented by O, S, and CR, respectively. 4 or C(R) 4 )2; Y is N, C(R) 5 )2 or CR 5 ;

[0018] Each R 4 and each R 5 Each is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is influenced by one or more R. 4-1 Substituted C1-C6 alkyl groups; each R 4-1 Each is independently either D or halogen;

[0019] Or, R 4 and R 5 Together with the carbon atoms directly bonded to it, a ternary saturated carbon ring is formed, which may optionally be bonded by one or more R atoms. 4-2 Replace; each R 4-2 Each is independently either D or halogen;

[0020] It is either a single bond or a double bond, and both (between X and Y) Between Y and Z They are not both double bonds;

[0021] When one of them When it is a double bond, X and Z are independently O, S, and CR, respectively. 4 or C(R) 4 )2; Y is N or CR 5 And when X and Z are both CR 4 or C(R) 4 )2 (i.e., X is CR) 4 Z is C(R) 4 )2, or X is C(R) 4 2. Z is CR 4 (When), Y is not N; where each R 4 and each R 5 Each is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is influenced by one or more R. 4-1 Substituted C1-C6 alkyl groups; each R 4-1 Each is independently either D or halogen;

[0022] When two When all bonds are single bonds, it falls under case (1) or (2):

[0023] Case (1): X is O or S; Y is C(R) 5 )2; Z is C(R) 4 )2; where each R 4 and each R 5 Each is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is influenced by one or more R. 4-1 Substituted C1-C6 alkyl groups; each R 4-1 Each is independently either D or halogen;

[0024] Case (2): One of X and Z is O or S; the other is CHR. 4 Y is CHR 5 ;where R 4 and R 5 Together with the carbon atoms directly bonded to it, a ternary saturated carbon ring is formed, which may optionally be bonded by one or more R atoms. 4-2 Replace, each R 4-2 Each is independently D or halogen (R) 4-2 It can replace any position in a ternary saturated carbon ring, such as R. 4-2 Replace CHR 4 H, or R 4-2 Replace CHR 5 H in; with Such structures formed For example, -D means replacing CHR. 4 (H in the middle).

[0025] The present invention also provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof.

[0026] in,

[0027] n is 0, 1, 2, or 3;

[0028] Each R 1 Each is independently D, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is associated with one or more R. 1-1 Substituted C1-C6 alkyl groups;

[0029] Each R 1-1 Each is independently either D or halogen;

[0030] R 2 It is a methyl group or a methyl group substituted with 1-3 D atoms;

[0031] R 3 C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with one or more R 3-1 C1-C6alkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted with one or more R 3-2 C1-C6alkyl;

[0032] each R 3-1 is independently D, halogen, or C1-C6alkyl;

[0033] each R 3-2 is independently D or halogen;

[0034] X and Z are each independently O, S, CR 4 , or C(R 4 )2; Y is N, C(R 5 )2, or CR 5 ;

[0035] each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen;

[0036] or, R 4 and R 5 together with the carbon atom to which they are directly attached form a three-membered saturated carbocyclic ring, which can be optionally substituted with one or more R 4-2 ; each R 4-2 is independently D or halogen;

[0037] is a single or double bond, and both (X and Y between and Y and Z between ) are not simultaneously double bonds;

[0038] when one of is a double bond, X and Z are each independently O, S, CR 4 , or C(R 4 )2; Y is N or CR 5 , and when X, Z are simultaneously CR 4 , or C(R 4 )2(i.e., X is CR 4 , Z is C(R 4 )2, or X is C(R 4 )2, Z is CR 4(When), Y is not N; where each R 4 and each R 5 Each is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is influenced by one or more R. 4-1 Substituted C1-C6 alkyl groups; each R 4-1 Each is independently either D or halogen;

[0039] When two When all bonds are single bonds, it falls under case (1) or (2):

[0040] Case (1): X is O or S; Y is C(R) 5 )2; Z is C(R) 4 )2; where each R 4 and each R 5 Each is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is influenced by one or more R. 4-1 Substituted C1-C6 alkyl groups; each R 4-1 Each is independently either D or halogen;

[0041] Case (2): One of X and Z is O or S; the other is CHR. 4 Y is CHR 5 ;where R 4 and R 5 Together with the carbon atoms directly bonded to it, a ternary saturated carbon ring is formed, which may optionally be bonded by one or more R atoms. 4-2 Replace, each R 4-2 Each is independently D or halogen (R) 4-2 It can replace any position in a ternary saturated carbon ring, such as R. 4-2 Replace CHR 4 H, or R 4-2 Replace CHR 5 H in; with Such structures formed For example, -D means replacing CHR. 4 (H in the middle).

[0042] In the compounds of the present invention or their pharmaceutically acceptable salts, certain groups have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in some embodiments").

[0043] In some implementation schemes, R 1 In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0044] In some implementation schemes, R 1C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl, and C1-C6alkyl in substituted C1-C6alkyl are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably methyl. 1- 1 C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl, and C1-C6alkyl in substituted C1-C6alkyl are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably methyl.

[0045] In some embodiments, R 1A In some embodiments, R

[0046] In some embodiments, R 1A C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl, and C1-C6alkyl in substituted C1-C6alkyl are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably methyl. 1- 1 C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl, and C1-C6alkyl in substituted C1-C6alkyl are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably methyl.

[0047] In some embodiments, R 1-1 In some embodiments, R

[0048] In some embodiments, R 2 In some embodiments, R

[0049] In some embodiments, R 3 C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl, and C1-C6alkyl in substituted C1-C6alkyl are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably methyl. 3-2 C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl, and C1-C6alkyl in substituted C1-C6alkyl are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably methyl.

[0050] In some embodiments, R 3 C3-C8cycloalkyl, and C3-C8cycloalkyl in substituted C3-C8cycloalkyl are each independently C3-C6monocyclic cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, more preferably cyclopropyl. 3-1 C3-C8cycloalkyl, and C3-C8cycloalkyl in substituted C3-C8cycloalkyl are each independently C3-C6monocyclic cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, more preferably cyclopropyl.

[0051] In some embodiments, R 3-1 In some embodiments, R

[0052] In some embodiments, R 3-1In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, preferably methyl.

[0053] In some implementation schemes, R 3-2 In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0054] In some implementation schemes, R 4 and R 5 In the context of C1-C6 alkyl, -O-C1-C6 alkyl, and C1-C6 alkyl and R 4-1 The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, preferably methyl.

[0055] In some implementation schemes, R 4 and R 5 In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0056] In some implementation schemes, R 4-1 In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0057] In some implementation schemes, R 4-2 In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0058] In some implementations, in Formula V, "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0059] In some implementations, in Formula I, "one or more" refers to 1, 2, 3 or 4, preferably 1 or 2.

[0060] In some implementations, n is 0 or 1, preferably 1.

[0061] In some implementations, m is 0, 1, 2, 4 or 6, preferably 0, 2, 4 or 6.

[0062] In some implementation schemes, each R 1 Each of the components is independently a halogen, an -O-C1-C6 alkyl group, or a C1-C6 alkyl group substituted with one or more halogens, preferably a halogen, and more preferably a fluorine.

[0063] In some implementation schemes, each R 1A Each is independently D, -OH, halogen, -O-C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens, preferably D or -OH.

[0064] In some embodiments, R 2 is methyl or methyl substituted with three D, preferably methyl.

[0065] In some embodiments, R' is H.

[0066] In some embodiments, R 3 is C1-C6 alkyl, C3-C6 monocyclic cycloalkyl substituted with one or more R 3-1 , -Si(C1-C6 alkyl)3, or C1-C6 alkyl substituted with one or more R 3-2 , preferably C1-C6 alkyl, -Si(C1-C6 alkyl)3, or C3-C6 monocyclic cycloalkyl substituted with one or more R 3- 1 , further preferably tert-butyl, ethyl, more preferably tert-butyl or most preferably tert-butyl.

[0067] In some embodiments, R 3 is C1-C6 alkyl, -Si(C1-C6 alkyl)3, or C3-C6 monocyclic cycloalkyl substituted with one or more R 3-1 ; preferably tert-butyl, ethyl, more preferably tert-butyl or most preferably tert-butyl.

[0068] In some embodiments, each R 3-1 is independently C1-C6 alkyl, preferably methyl.

[0069] In some embodiments, each R 3-2 is independently D or fluoro, preferably D.

[0070] In some embodiments, when one of is a double bond, is wherein X is CR 4 ; Y is N or CR 5 ; Z is O, S, or C(R 4 )2; and when X is CR 4 and Z is C(R 4 )2, Y is not N; each R 4 and each R 5 is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen.

[0071] In some embodiments, when one of is a double bond, is wherein X is CR 4 ; Y is CR 5 ; Z is O, S, or C(R 4 )2; each R 4 and each R 5 is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen.

[0072] In some embodiments, when one of is a double bond, is wherein X is CR 4 , Y is CR 5 ; Z is O; each R 4 and each R 5 is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen.

[0073] In some embodiments, when one of is a double bond, is wherein X is O, S, or C(R 4 )2; Y is N or CR 5 ; Z is CR 4 ; and when X is C(R 4 )2and Z is CR 4 , Y is not N; each R 4 and each R 5 is independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen.

[0074] In some embodiments, when one of is a double bond, is wherein X is O, S, or C(R 4 )2; Y is CR 5 ; Z is CR 4 ; each R 4 and each R5 each independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 each independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 each independently D or halogen.

[0075] In some embodiments, when one of is a double bond, is wherein X is O; Y is CR 5 ; Z is CR 4 ; each R 4 and each R 5 each independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 each independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 each independently D or halogen.

[0076] In some embodiments, when both of are single bonds, is wherein X is O or S; Y is C(R 5 )2; Z is C(R 4 )2; each R 4 and each R 5 each independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 each independently H, D, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-1 each independently D or halogen.

[0077] In some embodiments, when both of are single bonds, is X and Z are each independently O or S; o is 0, 1, 2, 3, or 4, preferably 0 or 2; each R 4-2 each independently D or halogen, preferably D or fluorine.

[0078] In some embodiments, is

[0079] wherein o is 0, 1, 2, 3, or 4, preferably 0 or 2; wherein denotes a ring formed by the bond with the phenyl group and the ring (the fragment is connected to the phenyl group in the parent nucleus from left to right, e.g. denotes denotes ).

[0080] In some embodiments, each R 4 each independently H, D, fluoro, or methyl, preferably H or D.

[0081] In some embodiments, each R 5 each independently H, D, fluoro, or methyl, preferably H or D.

[0082] In some embodiments, each R 4-1 each independently D or fluoro, preferably D.

[0083] In some embodiments, each R 4-2 each independently D or fluoro, preferably D.

[0084] In some embodiments, is wherein denotes a ring formed by the bond to the phenyl group and the ring (the fragment is connected to the phenyl group in the core from left to right, e.g. denotes denotes ).

[0085] In some embodiments, is wherein n is 0, 1, 2, or 3, each R 1 each independently D, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; m is 0, 1, 2, 3, 4, 5, or 6 (preferably 0, 2, 4, or 6), each R 1A each independently D, -OH, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens (preferably, R 1 is halogen (e.g., fluoro), R 1A is D or -OH).

[0086] In some embodiments, is wherein n is 0 or 1, each R 1 each independently D, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens.

[0087] In some embodiments, the compound of Formula V is a compound of Formula V-1, V-2, V-3, V-4, or V-5:

[0088] wherein Z is O, S, or C(R 4 )2; X is O, S, or C(R 4 )2; X' is O or S; o is 0, 1, 2, 3, or 4; n, m, R 1 , R 1A , R 2 , R', R 3 , R 4 , R 5 , and R 4-2 are as previously described.

[0089] In some embodiments, the compound of Formula V is any one of the following:

[0090] (1) the compound of Formula V-1,

[0091] n is 0 or 1, preferably 1;

[0092] m is 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, 4, or 6;

[0093] R 1 is halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen, preferably halogen (e.g., fluorine);

[0094] each R 1A is independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen, preferably D or -OH;

[0095] R 2 is methyl or methyl substituted with 1-3 D, preferably methyl;

[0096] R' is H or D, preferably H;

[0097] R 3 is Ci-C6alkyl, C3-C6monocyclic cycloalkyl substituted with one or more R 3-1 , -Si(Ci-C6alkyl)3, or Ci-C6alkyl substituted with one or more R 3-2 , preferably Ci-C6alkyl or Ci-C6alkyl substituted with one or more R 3-2 , more preferably Ci-C6alkyl;

[0098] each R 3-1 is independently Ci-C3alkyl, preferably methyl;

[0099] each R 3-2 is independently D or fluorine, preferably D;

[0100] Z is O, S or C(R 4 )2;

[0101] each R 4 is independently H, D, halogen or Ci-C6alkyl;

[0102] R 5 is H, D, halogen or Ci-C6alkyl;

[0103] (2) in compounds of formula V-2,

[0104] n is 0 or 1, preferably 1;

[0105] m is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 4 or 6;

[0106] R 1 is halogen, -O-Ci-C6alkyl or Ci-C6alkyl substituted by one or more halogen, preferably halogen (e.g. fluorine);

[0107] each R 1A is independently D, -OH, halogen, -O-Ci-C6alkyl or Ci-C6alkyl substituted by one or more halogen, preferably D or -OH;

[0108] R 2 is methyl or methyl substituted by 1-3 D, preferably methyl;

[0109] R' is H or D, preferably H;

[0110] R 3 is Ci-C6alkyl, C3-C6monocyclic cycloalkyl substituted by one or more R 3-1 , -Si(Ci-C6alkyl)3 or Ci-C6alkyl substituted by one or more R 3-2 , preferably Ci-C6alkyl or Ci-C6alkyl substituted by one or more R 3-2 , more preferably Ci-C6alkyl;

[0111] each R 3-1 is independently Ci-C3alkyl, preferably methyl;

[0112] each R 3-2 is independently D or fluorine, preferably D;

[0113] X is O, S or C(R 4 )2;

[0114] each R 4 is independently H, D, halogen or Ci-C6alkyl;

[0115] R 5 is H, D, halogen or C1-C6 alkyl;

[0116] (3) in compounds of formula V-3,

[0117] n is 0 or 1, preferably 1;

[0118] m is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 4 or 6;

[0119] R 1 is halogen, -O-C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogen, preferably halogen (e.g. fluorine);

[0120] each R 1A is independently D, -OH, halogen, -O-C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogen, preferably D or -OH;

[0121] R 2 is methyl or methyl substituted by 1-3 D, preferably methyl;

[0122] R’ is H or D, preferably H;

[0123] R 3 is C1-C6 alkyl, C3-C6 monocyclic cycloalkyl substituted by one or more R 3-1 , -Si(C1-C6 alkyl)3 or C1-C6 alkyl substituted by one or more R 3-2 , preferably C1-C6 alkyl or C1-C6 alkyl substituted by one or more R 3-2 , more preferably C1-C6 alkyl;

[0124] each R 3-1 is independently C1-C3 alkyl, preferably methyl;

[0125] each R 3-2 is independently D or fluorine, preferably D;

[0126] X’ is O or S;

[0127] each R 4 is independently H, D, halogen or C1-C6 alkyl;

[0128] each R 5 is independently H, D, halogen or C1-C6 alkyl;

[0129] (4) in compounds of formula V-4 and V-5,

[0130] n is 0 or 1, preferably 1;

[0131] m is 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, 4, or 6;

[0132] R 1 is halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen, preferably halogen (e.g., fluorine);

[0133] each R 1A is independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen, preferably D or -OH;

[0134] R 2 is methyl or methyl substituted with 1-3 D, preferably methyl;

[0135] R' is H or D, preferably H;

[0136] R 3 is Ci-C6alkyl, C3-C6monocyclic cycloalkyl substituted with one or more R 3-1 , -Si(Ci-C6alkyl)3, or Ci-C6alkyl substituted with one or more R 3-2 , preferably Ci-C6alkyl or Ci-C6alkyl substituted with one or more R 3-2 , more preferably Ci-C6alkyl;

[0137] each R 3-1 is independently Ci-C3alkyl, preferably methyl;

[0138] each R 3-2 is independently D or fluorine, preferably D;

[0139] o is 0, 1, 2, 3, or 4, preferably 0 or 2;

[0140] each R 4-2 is independently D or halogen, preferably D or F.

[0141] In some embodiments, the compound of Formula I is a compound of Formula I-1, Formula I-2, Formula I-3, Formula I-4, or Formula I-5:

[0142] wherein Z is O, S, or C(R 4 )2; X is O, S, or C(R 4 )2; X' is O or S; n, R 1 , R 2 , R 3 , R 4 , R 5 , R4-2 and o are as defined above.

[0143] In some embodiments, the compound of Formula I is any one of the following:

[0144] (1) in the compound of Formula I-1,

[0145] n is 0 or 1;

[0146] R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens;

[0147] R 2 methyl or methyl substituted with 1-3 D;

[0148] R 3 Ci-C6alkyl, C3-C6monocyclic cycloalkyl substituted with one or more R 3-1 , or -Si(Ci-C6alkyl)3;

[0149] each R 3-1 is each independently Ci-C3alkyl, preferably methyl;

[0150] Z is O, S, or C(R 4 )2

[0151] each R 4 is each independently H, D, halogen, or Ci-C6alkyl;

[0152] R 5 is H, D, halogen, or Ci-C6alkyl.

[0153] (2) in the compound of Formula I-2,

[0154] n is 0 or 1;

[0155] R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens;

[0156] R 2 methyl or methyl substituted with 1-3 D;

[0157] R 3 Ci-C6alkyl, C3-C6monocyclic cycloalkyl substituted with one or more R 3-1 , or -Si(Ci-C6alkyl)3;

[0158] each R 3-1 is each independently Ci-C3alkyl, preferably methyl;

[0159] X is O, S or C(R 4 )2

[0160] each R 4 is independently H, D, halogen or Ci-C6alkyl;

[0161] R 5 is H, D, halogen or Ci-C6alkyl.

[0162] (3) in compounds of formula I-3,

[0163] n is 0 or 1 ;

[0164] R 1 is halogen, -O-Ci-C6alkyl or Ci-C6alkyl substituted by one or more halogen;

[0165] R 2 is methyl or methyl substituted by 1-3 D;

[0166] R 3 is Ci-C6alkyl, C3-C6monocyclic cycloalkyl substituted by one or more R 3-1 or -Si(Ci-C6alkyl)3;

[0167] each R 3-1 is independently Ci-C3alkyl, preferably methyl;

[0168] X' is O or S;

[0169] each R 4 is independently H, D, halogen or Ci-C6alkyl;

[0170] each R 5 is independently H, D, halogen or Ci-C6alkyl.

[0171] (4) in compounds of formula I-4 and I-5,

[0172] n is 0 or 1 ;

[0173] R 1 is halogen, -O-Ci-C6alkyl or Ci-C6alkyl substituted by one or more halogen;

[0174] R 2 is methyl or methyl substituted by 1-3 D;

[0175] R 3 is Ci-C6alkyl, C3-C6monocyclic cycloalkyl substituted by one or more R 3-1 or -Si(Ci-C6alkyl)3;

[0176] each R3-1 Each is independently a C1-C3 alkyl group, preferably methyl;

[0177] o can be 0, 1, 2, 3 or 4, preferably 0 or 2;

[0178] Each R 4-2 Each can be either D or a halogen, with F being the preferred halogen.

[0179] In some embodiments, the compound represented by Formula I is any of the following:

[0180] (1) In the compound shown in Formula I-1,

[0181] n is 1;

[0182] R 1 It is a halogen; preferably F;

[0183] R 2 It is methyl;

[0184] R 3 For tert-butyl, Preferred to be tert-butyl;

[0185] Z is either O or CH2;

[0186] R 4 For H or D;

[0187] R 5 It can be H or D.

[0188] (2) In the compound shown in Formula I-2,

[0189] n is 1;

[0190] R 1 It is a halogen; preferably F;

[0191] R 2 It is methyl;

[0192] R 3 For tert-butyl, Preferred to be tert-butyl;

[0193] X is either O or CH2;

[0194] R 4 For H or D;

[0195] R 5 It can be H or D.

[0196] (3) In the compounds shown in Formula I-3

[0197] n is 1;

[0198] R1 halogen; preferably F;

[0199] R 2 methyl;

[0200] R 3 tert-butyl, preferably tert-butyl;

[0201] X' is O;

[0202] R 4 H or D;

[0203] R 5 H or D.

[0204] (4) compounds as shown in formulae I-4 and I-5,

[0205] n is 1;

[0206] R 1 halogen; preferably F;

[0207] R 2 methyl;

[0208] R 3 tert-butyl, preferably tert-butyl;

[0209] o is 0.

[0210] In some embodiments, preferably

[0211] In some embodiments,

[0212] In some embodiments,

[0213] In some embodiments, the compound of the present application is any one of the following compounds:

[0214] The present application provides a compound as shown in formula III',

[0215] wherein R 2 , R', R 3 , X, Y and Z are as previously described.​​​

[0216] The present application provides a compound as shown in formula III,

[0217] wherein, n, R 2 , R 3 , X, Y and Z are as defined above.

[0218] In some embodiments, the compound as shown in formula III’ or formula III is any one of the following structures:

[0219] The present application provides a preparation method of a compound as shown in formula V or a pharmaceutically acceptable salt thereof, which comprises the following steps: performing a coupling reaction as shown below on a compound as shown in formula II’ or a salt thereof and a compound as shown in formula III’ in a solvent, preferably in the presence of a catalyst (preferably a Pd catalyst) and a base, to obtain a compound as shown in formula V;

[0220] wherein, n, R 1 , R 2 , R’, R 3 , X, Y and Z are as defined above.

[0221] The present application provides a preparation method of a compound as shown in formula I or a pharmaceutically acceptable salt thereof, which comprises the following steps: performing a coupling reaction as shown below on a compound as shown in formula II or a salt thereof and a compound as shown in formula III in a solvent, preferably in the presence of a catalyst (preferably a Pd catalyst) and a base, to obtain a compound as shown in formula I;

[0222] wherein, n, R 1 , R 2 , R 3 , X, Y and Z are as defined above.

[0223] In some embodiments, the salt of the compound as shown in formula II’ is a hydrochloride.

[0224] In some embodiments, the salt of the compound as shown in formula II is a hydrochloride.

[0225] In some embodiments, in the preparation method of the compound as shown in formula V and formula I, the solvent can be a conventional solvent for such reactions in the art, each independently preferably an organic solvent, more preferably a cyclic ether solvent, for example, dioxane and / or tetrahydrofuran, preferably dioxane.

[0226] In some embodiments, in the preparation method of the compound of formula V and formula I, the Pd catalyst can be a conventional Pd catalyst for such reactions in the art, each independently preferably (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) methanesulfonate, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium.

[0227] In some embodiments, in the preparation method of the compound of formula V and formula I, the base can be a conventional base for such reactions in the art, each independently preferably an inorganic base or a strong base weak acid salt, which can be cesium carbonate.

[0228] The present application provides a compound prepared by the above preparation method or a pharmaceutically acceptable salt thereof.

[0229] The present application provides a pharmaceutical composition comprising:

[0230] (1) a compound or a pharmaceutically acceptable salt thereof as described above or a compound prepared by the above preparation method or a pharmaceutically acceptable salt thereof, and

[0231] (2) a pharmaceutically acceptable excipient.

[0232] The present application provides a compound or a pharmaceutically acceptable salt thereof as described above, a compound prepared by the above preparation method or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use as a medicament.

[0233] The present application provides a compound or a pharmaceutically acceptable salt thereof as described above, a compound prepared by the above preparation method or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use as a KCNQ2 / 3 channel opener.

[0234] In some embodiments, the KCNQ2 / 3 channel opener can be used in vivo in a mammalian organism; it can also be used in vitro, mainly for experimental purposes, for example: as a standard or control sample to provide a comparison, or prepared into a kit according to conventional methods in the art, to provide a rapid detection of the opening effect of the KCNQ2 / 3 channel.

[0235] The present application provides a compound or a pharmaceutically acceptable salt thereof as described above, a compound prepared by the above preparation method or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the preparation of a medicament for preventing or treating a disease.

[0236] In some embodiments, the disease is epilepsy, depression, anxiety or pain.

[0237] In some embodiments, the epilepsy includes, but is not limited to, focal seizures or generalized convulsive seizures.

[0238] The present application provides use of a compound as described above or a pharmaceutically acceptable salt thereof, a compound prepared by a method as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for preventing or treating a disease associated with KCNQ2 / 3 channel.

[0239] In some embodiments, the disease associated with KCNQ2 / 3 channel can be epilepsy, depression, anxiety or pain.

[0240] In some embodiments, the epilepsy includes, but is not limited to, focal seizures or generalized convulsive seizures.

[0241] The present application provides a method for preventing or treating a disease associated with KCNQ2 / 3 channel, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof, a compound prepared by a method as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0242] In some embodiments, the disease associated with KCNQ2 / 3 channel can be epilepsy, depression, anxiety or pain.

[0243] In some embodiments, the epilepsy includes, but is not limited to, focal seizures or generalized convulsive seizures.

[0244] Explanation of terms

[0245] In the present application, the term "pharmaceutically acceptable salt" refers to a salt of a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functionality, a base addition salt can be obtained by contacting the compound with a sufficient amount of the pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functionality, an acid addition salt can be obtained by contacting the compound with a sufficient amount of the pharmaceutically acceptable acid in a suitable inert solvent. For details see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0246] In the present application, the structure fragment in is connected to the rest of the molecule through the site. For example, "-" means that the group is attached to the remainder of the molecule at this point.

[0247] In the present application, the "-" at the end of a group means that the group is attached to the remainder of the molecule at this point. For example, -OH means that the hydroxyl group is attached to the remainder of the molecule at this point.

[0248] In the present application, the term "one or more" means 1 or more than 1, for example 1, 2, 3, 4, etc., preferably 1 or 2.

[0249] In the present application, the term "group B substituted with one or more groups A" means that the groups A can be located at the same position or at different positions of group B when groups A are "plural".

[0250] In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0251] In the present application, the term "alkyl" means a saturated, straight-chain or branched-chain, monovalent hydrocarbon group having a specified number of carbon atoms. C1-C6 alkyl means an alkyl group having 1-6 (e.g. 1, 2, 3, 4, 5, 6) carbon atoms, including C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0252] In the present application, the term "cycloalkyl" means a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g. C3-C8, C5-C7). It is a monocyclic or polycyclic (e.g. polycyclic is 2 or 3 rings). When the "cycloalkyl" is polycyclic, it is a spirocyclic cycloalkyl, a fused cyclic cycloalkyl or a bridged cyclic cycloalkyl, and the like, preferably a spirocyclic cycloalkyl which shares one carbon atom between the monocyclic rings. Cycloalkyl groups include, but are not limited to:

[0253] In the present application, the term "saturated carbocycle" means a saturated carbocycle having a specified number of carbon ring atoms (e.g. 3- to 8-membered, 5- to 7-membered). It is a monocyclic. "Saturated carbocycle" includes, but is not limited to:

[0254] ​​In the present application, the term "pharmaceutically acceptable excipients" refers to all substances contained in a pharmaceutical preparation in addition to the active pharmaceutical ingredient, which are generally divided into two categories of excipients and additional agents. For specific reference, see the People's Republic of China Pharmacopoeia (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0255] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain various preferred examples of the present application.

[0256] The reagents and raw materials used in the present application are commercially available.

[0257] The positive progress effect of the present application is that the potassium channel modulator compound of the present application has one or more of the following effect advantages: (1) novel structure; (2) good KCNQ2 / 3 channel opening activity; (3) weak KCNQ4, KCNQ5 opening activity, high KCNQ2 / 3 selectivity; (4) good in vivo efficacy, good protection effect on seizures; (5) low neurotoxicity; (6) high brain blood ratio; (7) high plasma, brain tissue concentration. The more optimal compound and the most optimal compound of the present application have two or more of the above-mentioned effect advantages. DETAILED DESCRIPTION

[0258] The present application is further described below, but the present application is not limited in the scope described. The experimental methods in the following preparation examples without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0259] Preparation Example 1: Synthesis of compounds S-001a and S-001b

[0260] Step 1: Synthesis of intermediate 1-2

[0261] Compound 1-1 (500 mg, 2.36 mmol) was dissolved in 8 mL of methanol, and N-iodosuccinimide (530.41 mg, 2.36 mmol) was added. The reaction system was stirred at 25°C for 1 hour. TLC (petroleum ether / ethyl acetate = 7:1) was used to monitor the complete consumption of the raw material. The reaction system was quenched with 4 mL of saturated sodium bicarbonate solution, and the organic phase was extracted with ethyl acetate (6 mL x 2). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 7:1) to obtain the target compound 1-2 (500 mg, 2.36 mmol, 100% yield). 20g Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to afford intermediate 1-2 as a grey black solid (780 mg, yield: 97.89%). LCMS (ESI): m / z C9H 10 BrIN + [M+H]+. [M-H]-. + Calculated = 337.90, 339.90, Found = 337.9, 339.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.47 (s, 1 H), 5.04 (s, 2 H), 2.88-2.68 (m, 4 H), 2.06-1.94 (m, 2 H); 13 C NMR (101 MHz, DMSO) δ ppm 144.80, 144.28, 137.74, 129.83, 105.71, 81.18, 34.82, 32.48, 23.72.

[0262] Step 2: Synthesis of intermediate 1-3

[0263] Intermediate 1-2 (600 mg, 1.78 mmol) was dissolved in 10 mL of dichloromethane and triethylamine (359.27 mg, 3.55 mmol, 494.19 μί) was added. To the above solution, compound 1-2a (477.91 mg, 3.55 mmol, 493.20 μί) was added dropwise with stirring. After the addition was completed, the reaction system was stirred at 25 °C for 1 h. TLC (petroleum ether / ethyl acetate = 6: 1) monitoring showed that the raw material was consumed completely and the product spot was generated. The reaction liquid was concentrated to a residue under reduced pressure and purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to afford intermediate 1-3 as a white solid (710 mg, yield: 91.89%). LCMS (ESI): m / z C 12g Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to afford intermediate 1-2 as a grey black solid (780 mg, yield: 97.89%). LCMS (ESI): m / z C9H 15 H 20 BrIN + [M+H]+. [M-H]-. + Calculated = 337.90, 339.90, Found = 337.9, 339.9. 1 H NMR (400 MHz, DMSO) δ ppm 7.47 (s, 1 H), 5.04 (s, 2 H), 2.88-2.68 (m, 4 H), 2.06-1.94 (m, 2 H); 13C NMR (101 MHz, DMSO-d6) δ ppm 169.63, 145.64, 145.12, 138.41, 136.64, 117.92, 97.99, 48.93, 34.88, 33.83, 31.18, 30.36, 23.74.

[0264] Step 3: Synthesis of Intermediate 1-4

[0265] Intermediate 1-3 (16.5 g, 37.8 mmol) was dissolved in 200 mL of acetone and 15% aqueous magnesium sulfate solution (42.53 mL) was added. The system was added with potassium permanganate (14.95 g, 94.5 mmol) in batches under stirring. The reaction system was stirred at 25 °C for 5 hours. 15% Aqueous magnesium sulfate solution (42.53 mL) and potassium permanganate (14.95 g, 94.5 mmol) were added again. The reaction system was continuously stirred at 25 °C for 12 hours. LCMS monitoring showed that the raw material was completely reacted. The reaction solution was filtered, the filtrate was concentrated to a residue, and the residue was prepared by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 1-4 as a light yellow solid (9.2 g, yield: 54.07%). 220 g Silica Flash Column, mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 1-4 as a light yellow solid (9.2 g, yield: 54.07%). 15 H 18 BrINO2 + [M+H] + Calculated = 449.96, 451.95. Found = 449.9, 451.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 8.33 (s, 1H), 2.97-2.84 (m, 2H), 2.69-2.58 (s, 2H), 2.24 (s, 2H), 1.08 (s, 9H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 202.55, 170.35, 155.92, 145.75, 137.68, 131.81, 120.29, 100.79, 49.08, 36.61, 31.28, 30.42, 26.33.

[0266] Step 4: Synthesis of Intermediate 1-5

[0267] Intermediate 1-4 (4.80 g, 10.7 mmol) was dissolved in 48 mL of 1,4-dioxane, and 1-4a methylboronic acid (1.28 g, 21.3 mmol), tetrakis(triphenylphosphine)palladium (1.85 g, 1.60 mmol), cesium carbonate (10.51 g, 32.0 mmol) were added successively. The reaction system was replaced with nitrogen three times, and was heated to 100 °C under nitrogen protection. The reaction was stirred for 2 hours. After the raw material was detected by LCMS, the reaction liquid was filtered, the filter cake was washed with ethyl acetate (5 mL), and the filtrate was evaporated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 40~30) to obtain intermediate 1-5 as a white solid (760 mg, yield: 21.07%). 16 H 21 BrNO2 + [M+H] + Calcd = 338.08, 340.07, Found = 338.1, 340.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H), 7.79 (s, 1H), 2.96-2.83 (m, 2H), 2.67-2.59 (m, 2H), 2.24 (s, 2H), 2.18 (s, 3H), 1.05 (s, 9H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 201.18, 170.07, 152.91, 139.11, 136.61, 133.81, 133.16, 118.17, 49.21, 37.00, 31.18, 30.21, 26.02, 17.75.

[0268] Step 5: synthesis of intermediate 1-6

[0269] Intermediate 1-5 (0.5 g, 1.48 mmol) was dissolved in 50 mL of methanol, and the system was cooled to 0 °C, and sodium borohydride (0.18 g, 4.75 mmol) was added in batches. The reaction system was stirred at 0 °C for 1 hour. LCMS detected that the raw material was completely consumed, and the product was generated. 10% of ammonium chloride solution (10 mL) was added dropwise to the reaction liquid. The reaction was continued to stir for 30 minutes. The system was concentrated under reduced pressure, and the residue was diluted with 100 mL of dichloromethane and 50 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 40~30) to obtain intermediate 1-6 as a white solid (0.3 g, yield: 63.33%). 20g Intermediate 1-6 was prepared as a white solid (460 mg, yield: 91.34%) from Silica Flash Column, mobile phase gradient: 0-70% ethyl acetate / petroleum ether; flow rate: 20 mL / min) by the method. LCMS (ESI): m / z C 16 H 23 BrNO2 + [M+H]. [M+Na]. + Calculated = 340.09, 342.09. Found = 340.1, 342.1.

[0270] Step 6: Synthesis of intermediate 1-7

[0271] Intermediate 1-6 (450 mg, 1.32 mmol) was dissolved in 45 mL of toluene and p-toluenesulfonic acid (45.5 mg, 0.26 mmol) was added. The reaction system was heated to reflux with stirring for 2 hours. LCMS monitoring of raw material consumption was safe, and the reaction was cooled to room temperature, 10 mL of saturated sodium bicarbonate solution was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic phase was combined, washed with water (10 mL x 2), saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was prepared by silica gel column chromatography to obtain intermediate 1-7 as a light yellow solid powder (280 mg, yield: 65.83%). LCMS (ESI): m / z C 16 H 21 BrNO + [M+H]. [M+Na]. + Calculated = 322.08, 324.08. Found = 322.1, 324.1. 1 H NMR (400 MHz, CDC13) δ ppm 7.23 (s, 1 H), 6.85-6.78 (m, 2 H), 6.60 (d, J = 5.5 Hz, 1 H), 3.39 (s, 2 H), 2.33 (s, 2 H), 2.29 (s, 3 H), 1.17 (s, 9 H).

[0272] Step 7: Synthesis of compounds S-001a and S-001b

[0273] Intermediate 1-7 (170 mg, 527.56 µmol) and compound 1-7a (395.97 mg, 2.11 mmol) were dissolved with 18 mL of dioxane, and RuPhos Pd G3 (44.12 mg, 52.76 µmol), cesium carbonate (859.45 mg, 2.64 mmol) were added in turn. The reaction system was vacuumed and replaced with nitrogen for three times. The system was stirred at 120 °C for 4 hours under the protection of nitrogen. TLC (petroleum ether: ethyl acetate = 3:1) was used to monitor the consumption of raw materials. LCMS was used to monitor the generation of two products. The reaction system was filtered, the filtrate was concentrated to a residue under reduced pressure, and compound S-001a was prepared by reverse phase column chromatography (column specification: Welch Xtimate C18 150×30 mm; particle size: 5 µm; mobile phase: [A phase: water (0.225% formic acid)-B phase: acetonitrile]; gradient: 53%-83% B, for 9 minutes) as a white solid (10 mg, yield: 4.82%). LCMS (ESI): m / z C 25 H 30 FN2O + [M+H]+. Found: 393.3. + Calc. = 393.23, Found = 393.4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 7.27-7.18 (m, 1H), 7.06-6.96 (m, 2H), 6.75 (s, 1H), 6.72 (d, J = 5.6 Hz, 1H), 6.53 (d, J = 5.5 Hz, 1H), 4.23 (s, 2H), 3.43 (s, 2H), 3.39-3.37 (m, 2H), 2.95 (t, J = 5.3 Hz, 2H), 2.22 (s, 2H), 2.17 (s, 3H), 1.07 (s, 9H). Meanwhile, compound S-001b was prepared as a white solid (30 mg, yield: 14.48%). LCMS (ESI): m / z C 25 H 30 FN2O + [M+H]+. Found: 393.3. + Calc. = 393.23, Found = 393.4. 1H NMR (400 MHz, DMSO-d6) d ppm 9.21 (s, 1 H), 7.27-7.20 (m, 1 H), 7.06-6.99 (m, 2 H), 6.94 (d, J = 5.5 Hz, 1 H), 6.82 (s, 1 H), 6.50 (d, J = 5.5 Hz, 1 H), 4.19 (s, 2 H), 3.32-3.30 (m, 2 H), 3.26 (s, 2 H), 3.02 (t, J = 5.5 Hz, 2 H), 2.22 (s, 2 H), 2.20 (s, 3 H), 1.08 (s, 9 H).

[0274] Preparation Example 2: Synthesis of compound S-002

[0275] Step 1: Synthesis of intermediate 2-2

[0276] Compound 2-1 (10.0 g, 81.2 mmol) was dissolved in 150 mL of dichloromethane, and diisopropylethylamine (31.48 g, 244 mmol) was added. The reaction system was cooled to 0°C, and compound 1-2a (11.48 g, 85.3 mmol) was added dropwise into the above solution. After the addition was completed, the reaction system was continuously stirred at 0°C for 1 hour. LCMS monitoring showed that the raw material was substantially completely consumed. The reaction liquid was quenched with 80 mL of water, and the organic phase was separated, washed with water (60 mL x 2) and saturated brine (50 mL x 2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:2) to obtain intermediate 2-2 as a white solid (8.36 g, yield: 46.52%). 13 H 20 NO2 + [M+H] + Calculated = 222.15, Found = 222.1. 1 H NMR (400 MHz, DMSO-d6) d ppm 9.12 (s, 1 H), 8.97 (s, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.91 (d, J = 2.4 Hz, 1 H), 6.47 (dd, J = 8.2, 2.5 Hz, 1 H), 2.20 (s, 2 H), 2.08 (s, 3 H), 1.04 (s, 9 H); 13 C NMR (101 MHz, DMSO-d6) d ppm 170.10, 155.68, 137.52, 131.03, 121.67, 112.43, 49.53, 31.17, 30.16, 17.61.

[0277] Step 2: Synthesis of intermediate 2-3

[0278] Intermediate 2-2 (4.43 g, 20 mmol) was dissolved in 45 mL of ethanol, the system was cooled to 0 °C, and N-bromosuccinimide (3.74 g, 21 mmol) was added in batches. The reaction system was stirred at 0 °C for 1 h. LCMS monitoring showed that the raw material was completely reacted. The reaction liquid was added dropwise into 5% sodium sulfite aqueous solution (120 mL), and light yellow solid was precipitated during the dropwise addition. After the dropwise addition was completed, it was stood for 10 min, and then filtered, the filter cake was washed with 40 mL of water, and dried to give intermediate 2-3 as a light yellow solid (5.80 g, yield: 96.6%). LCMS (ESI): m / z C 13 H 19 BrNO2 + [M+H]. [M+Na]. + Calcd = 300.06, 302.06, Found = 299.9, 301.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1 H), 9.03 (s, 1 H), 7.28 (s, 1 H), 7.18 (s, 1 H), 2.21 (s, 2 H), 2.09 (s, 3 H), 1.03 (s, 9 H); 13 CNMR (101 MHz, DMSO-d6) δ ppm 170.25, 152.16, 136.97, 133.79, 123.64, 113.02, 104.96, 49.44, 31.20, 30.13, 17.21.

[0279] Step 3: synthesis of intermediate 2-4

[0280] Intermediate 2-3 (3.00 g, 10 mmol) was dissolved in 30 mL of N,N-dimethylacetamide, and intermediate 2-3a (2.36 g, 12 mmol) and potassium carbonate (2.76 g, 20 mmol) were added. The reaction system was stirred at 120 °C for 7 h. LCMS monitoring showed that the raw material was substantially consumed. The reaction liquid was cooled to room temperature, then 10 mL of ethanol and 90 mL of water were added, and light yellow solid slowly precipitated in the mixed solution. Filtration, the filter cake was washed with 30 mL of water, and dried to give intermediate 2-4 as a light yellow solid (3.2 g, yield: 76.85%). LCMS (ESI): m / z C 19 H 31 BrNO4 + [M+H]. [M+Na]. + Calcd = 416.14, 418.14. Found = 416.1, 418.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (s, 1 H), 7.40 (s, 1 H), 7.27 (s, 1 H), 4.81 (t, J = 5.2 Hz, 1 H), 3.93 (d, J = 5.2 Hz, 2 H), 3.75 - 3.50 (m, 4 H), 2.23 (s, 2 H), 2.13 (s, 3 H), 1.14 (t, J = 7.0 Hz, 6 H), 1.04 (s, 9 H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 170.36, 152.73, 137.33, 134.12, 125.69, 111.06, 106.69, 100.24, 70.03, 62.82, 49.49, 31.15, 30.14, 17.28, 15.77.

[0281] Step 4: synthesis of intermediate 2-5

[0282] Intermediate 2-4 (4.16 g, 10 mmol) was dissolved in 90 mL of toluene, and 85% phosphoric acid solution (6.9 mL) was added dropwise. The reaction system was heated to reflux with stirring for 3 hours. LCMS monitoring showed that the raw material was completely consumed. The system was diluted with 100 mL of ethyl acetate, filtered, and the filtrate was washed successively with water (50 mL x 2), saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:5) to give intermediate 2-5 as a white solid (1.1 g, yield: 33.93%). LCMS (ESI): m / z C 15 H 19 BrNO2 + [M+H] + Calculated = 324.06, 326.06, Found = 324.1, 326.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.60 (s, 1 H), 8.01 (s, 1 H), 7.44 (s, 1 H), 6.75 (s, 1 H), 2.28 (s, 2 H), 2.25 (s, 3 H), 1.08 (s, 9 H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 169.95, 150.38, 146.59, 130.07, 129.39, 129.09, 126.40, 107.56, 100.26, 49.18, 31.10, 30.23, 17.90.

[0283] Step 5: synthesis of compound S-002

[0284] Compound S-002 was prepared according to the procedure described in Step 7 of Preparation 1, by replacing the corresponding starting material with intermediate 2-5 as starting material. Compound S-002 was obtained as a white solid. LCMS (ESI): m / z C 24 H 28 FN2O2 + [M+H] + Calculated = 395.21, Found = 395.2. 1 H NMR (400 MHz, CD3OD) δ ppm 9.35 (s, 1 H), 7.88 (d, J = 2.1 Hz, 1 H), 7.26 (dd, J = 5.8, 9.4 Hz, 1 H), 7.06 - 6.99 (m, 2 H), 6.70 (s, 1 H), 6.62 (d, J = 2.1 Hz, 1 H), 4.40 (s, 2 H), 3.61 (t, J = 6.0 Hz, 2 H), 2.98 (t, J = 5.4 Hz, 2 H), 2.24 (s, 2 H), 2.21 (s, 3 H), 1.08 (s, 9 H).

[0285] Preparation 3: Synthesis of compound S-003

[0286] Step 1: Synthesis of intermediate 3-2

[0287] Compound 3-1 (3 g, 13.95 mmol) and compound 3-1a (13.10 g, 69.75 mmol, 5.26 mL) were dissolved in 100 mL of acetonitrile and potassium carbonate (1.93 g, 13.95 mmol) was added. The reaction was stirred at 100 °C for 2 h. TLC monitoring (petroleum ether: ethyl acetate = 10:1) showed that the starting material was consumed completely and the main product was generated. The reaction was filtered, the filtrate was concentrated to a residue under reduced pressure and the residue was purified by silica gel column chromatography (40 g 40 g Silica Flash Column, mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 100 mL / min) to give intermediate 3-2 as a colorless oil (800 mg, yield: 17.81%). 1 H NMR (400 MHz, CDCl3) δ ppm 10.45 (s, 1 H), 7.37 (d, J = 8.5 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 4.37 (t, J = 6.3 Hz, 2 H), 3.68 (t, J = 6.2 Hz, 2 H), 2.42 (s, 3 H).

[0288] Step 2: Synthesis of intermediate 3-3

[0289] Intermediate 3-2 (800 mg, 2.48 mmol) was dissolved in 9 mL of DMSO, and potassium tert-butoxide (278.79 mg, 2.48 mmol) was added. The reaction system was stirred at 30 °C for 2 hours. TLC (petroleum ether: ethyl acetate = 6:1) monitoring showed that the raw material was completely consumed, and the product was generated. The reaction liquid was diluted with 30 mL of water and 30 mL of ethyl acetate, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain intermediate 3-3 as a colorless oil (400 mg, yield: 66.78%). 20g Silica Flash Column, mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 100 mL / min) to obtain intermediate 3-3 as a colorless oil (400 mg, yield: 66.78%). 1 H NMR (400 MHz, CDC13) δ ppm 10.40 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.61 (dd, J = 6.1, 13.7 Hz, 1H), 4.78 (dd, J = 2.1, 13.8 Hz, 1H), 4.56 (dd, J = 2.0, 6.1 Hz, 1H), 2.44 (s, 3H).

[0290] Step 3: Synthesis of intermediate 3-4

[0291] Intermediate 3-3 (0.4 g, 1.66 mmol) was dissolved in 3 mL of ethanol, and p-toluenesulfonyl hydrazide (370.79 mg, 1.99 mmol) was added. The reaction system was stirred at 20 °C for 1 hour. LCMS monitoring showed that the raw material was substantially reacted completely, and white solid was precipitated from the system, which was filtered, the filter cake was washed with petroleum ether (5 mL), and dried to obtain intermediate 3-4 as a white solid (250 mg, yield: 36.81%). 17 H 18 BrN2O3S + [M+H] + Calculated = 409.02, 411.02. Found = 409.0, 411.0.

[0292] Step 4: Synthesis of intermediate 3-5

[0293] Intermediate 3-4 (200 mg, 488.64 pmol) was dissolved in 4 mL of toluene, and rhodium octanoate dimer (CAS: 73482-96-9) (38.05 mg, 48.86 pmol) and lithium tert-butoxide (46.94 mg, 586.37 pmol) were added. The reaction system was stirred at 100 °C for 2 hours. LCMS monitored the complete consumption of raw materials, and product was generated. The reaction liquid was concentrated to a residue under reduced pressure, and intermediate 3-5 was prepared as a colorless oil (95 mg, yield: 86.38%) by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-2% ethyl acetate / petroleum ether; flow rate: 30 mL / min). 20 g Silica Flash Column, mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give intermediate 3-6 as a colorless oil (101 mg, yield: 91.57%). LCMS (ESI): m / z C 1 H NMR (400 MHz, CDC13) δ ppm 6.86 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 4.74-4.71 (m, 1H), 2.76-2.53 (m, 1H), 2.25 (s, 3H), 1.05-0.90 (m, 1H), 0.33-0.29 (m, 1H).

[0294] Step 5: Synthesis of intermediate 3-6

[0295] Intermediate 3-5 (95 mg, 422.07 pmol) was dissolved in 3 mL of dioxane, and compound 3-5a (197.77 mg, 1.69 mmol), cesium carbonate (687.59 mg, 2.11 mmol), Pd2(dba)3 (77.30 mg, 84.41 pmol), and Xantphos (73.27 mg, 126.62 pmol) were added in turn. The reaction system was stirred at 105 °C for 12 hours. LCMS monitored the complete consumption of raw materials, and product was generated. The reaction liquid was filtered, and the filtrate was concentrated to a residue under reduced pressure, and intermediate 3-6 was prepared as a colorless oil (101 mg, yield: 91.57%) by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 30 mL / min). 20 g Silica Flash Column, mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give intermediate 3-6 as a colorless oil (101 mg, yield: 91.57%). LCMS (ESI): m / z C 15 H 20 NO3 + [M+H] + Calc. = 262.14, [M-t-Bu+H] + Found = 206.0.

[0296] Step 6: Synthesis of intermediate 3-7

[0297] Intermediate 3-6 (101 mg, 386.49 μmol) was dissolved in 5 mL of trifluoroacetic acid, and the reaction system was stirred at 20 °C for 10 min. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was concentrated under reduced pressure to obtain a residue, which was dissolved in 10 mL of ethyl acetate and washed with saturated sodium bicarbonate solution (5 mL x 2). After separation of the organic phase, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain intermediate 3-7 as a light yellow solid (93 mg, crude). LCMS (ESI): m / z C 10 H 12 NO + . [M+H] + Calcd = 162.09, Found = 162.0.

[0298] Step 7: Synthesis of intermediate 3-8

[0299] Compound 3-7 (93 mg, crude) was dissolved in 3 mL of DMF, and the system was cooled to 0 °C. N-bromosuccinimide (72.2 mg, 405.81 μmol) was dissolved in 0.5 mL of DMF, and then slowly added to the above reaction system, controlling the reaction temperature not to exceed 0 °C. After the addition was completed, the reaction was stirred for 30 min. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was added dropwise to saturated aqueous sodium bicarbonate solution (8 mL) to quench, and the system was extracted with ethyl acetate (5 mL x 3). After the organic phases were combined, they were successively washed with water (10 mL x 2) and saturated brine (5 mL x 2). After separation of the organic phase, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a residue, which was subjected to silica gel column chromatography (4 g 4g Silica Flash Column, mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 3-8 as a light brown solid (58 mg). LCMS (ESI): m / z C 10 H 11 BrNO + . [M+H] + Calcd = 240.00, 242.00, Found = 240.0, 242.0.

[0300] Step 8: Synthesis of intermediate 3-9

[0301] With reference to the synthesis method in step 2 of Preparation Example 1, the corresponding raw material was replaced, and intermediate 3-8 was used as the raw material to prepare intermediate 3-9 as a white solid. LCMS (ESI): m / z C 16 H 21 BrNO2 + . [M+H] +Calculated values ​​= 338.08, 340.07, measured values ​​= 338.0, 340.0.

[0302] Step 9: Synthesis of compound S-003

[0303] Following the synthetic method in step 5 of Preparation Example 2, and replacing the corresponding starting materials, using intermediates 3-9 as the starting material, compound S-003 was prepared as a white solid. LCMS(ESI): m / z C 25 H 30 FN2O2 + [M+H] + Calculated value = 409.23, measured value = 409.2.

[0304] Preparation Example 4: Synthesis of Compound S-004

[0305] Step 1: Synthesis of intermediate 4-2

[0306] Compound 4-1 (200 mg, 1.11 mmol) and compound 1-7a (416.56 mg, 2.22 mmol) were dissolved in 10 mL of acetonitrile, and cesium carbonate (723.50 mg, 2.22 mmol) was added. The reaction system was microwaved at 110 °C for 5 hours. LCMS monitoring showed that some starting material remained, and product formation was observed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then subjected to silica gel column chromatography. 20g Intermediate 4-2 was prepared by a Silica Flash Column (mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 40 mL / min) as a yellow solid (198.71 mg, yield: 57.30%). LCMS (ESI): m / z C 17 H 15 FN3O2 + [M+H] + Calculated value = 312.11, measured value = 312.2.

[0307] Step 2: Synthesis of intermediate 4-3

[0308] Intermediate 4-2 (198.71 mg, 638.31 μmol) was dissolved in 5 mL of ethanol, and iron powder (142.59 mg, 2.55 mmol) and 2 M ammonium chloride solution (1.28 mL) were added. The reaction system was stirred at 90 °C for 10 minutes. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain intermediate 4-3 as a brown solid (120 mg, crude product). LCMS (ESI): m / z C 17 H17 FN3 + [M+H]+ + Calcd = 282.14, Found = 282.3.

[0309] Step 3: Synthesis of compound S-004

[0310] Referring to the synthetic method of Step 2 in Preparation 1, replacing the corresponding raw material, intermediate 4-3 was used as the raw material to prepare compound S-004 as a light yellow solid. LCMS (ESI): m / z C 23 H 27 FN3O + [M+H]+ + Calcd = 380.21, Found = 380.4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.63 (s, 1H), 9.44 (s, 1H), 7.30 (t, J = 2.6 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.06 - 6.96 (m, 2H), 6.50 (d, J = 8.1 Hz, 1H), 6.47 - 6.42 (m, 1H), 4.24 (s, 2H), 3.43 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 5.3 Hz, 2H), 2.26 (s, 2H), 1.06 (s, 9H).

[0311] Preparation 5: Synthesis of compound S-005

[0312] Step 1: Synthesis of intermediate 5-2

[0313] Referring to the synthetic method of Step 2 in Preparation 1, replacing the corresponding raw material, compound 5-1 was used as the raw material to prepare intermediate 5-2 as a white solid. LCMS (ESI): m / z C 13 H 18 BrN2O3 + [M+H]+ + Calcd = 329.05, 331.05, Found = 329.0, 331.0. 1 H NMR (400 MHz, CDCl3) δ ppm (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 2H), 1.11 (s, 9H).

[0314] Step 2: Synthesis of intermediate 5-3

[0315] Intermediate 5-2 (2 g, 6.08 mmol) was dissolved in 15 mL of tetrahydrofuran, the system was cooled to -40 °C, and a solution of vinylmagnesium chloride in tetrahydrofuran (1.6 M, 18.99 mL) was slowly added dropwise to the above solution. After the dropwise addition was completed, the reaction system was stirred at -40 °C for 2 hours. LCMS monitoring showed that the product was generated. The reaction system was diluted with 100 mL of water and 100 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, and purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-80% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 5-3 as an off-white solid (59 mg, yield: 3.0%). LCMS (ESI): m / z C 40 g Silica Flash Column, mobile phase gradient: 0-80% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 5-3 as an off-white solid (59 mg, yield: 3.0%). LCMS (ESI): m / z C 15 H 20 BrN2O + [M+H]. [M+Na]. + Calcd = 323.08, 325.07, Found = 323.0, 325.0.

[0316] Step 3: Synthesis of compound S-005

[0317] Referring to the synthesis method of step 5 in Preparation Example 2, the corresponding raw material was replaced, and intermediate 5-3 was used as the raw material to prepare compound S-005 as a white solid. LCMS (ESI): m / z C 24 H 29 FN3O + [M+H]. [M+Na]. + Calcd = 394.23, Found = 394.3. 1 H NMR (400 MHz, CD3CN) δ ppm 8.99 (s, 1 H), 7.77 (s, 1 H), 7.10 (dd, J = 6.1, 7.9 Hz, 1 H), 7.04 (s, 1 H), 6.90-6.82 (m, 2 H), 6.40 (d, J = 8.7 Hz, 2 H), 4.28-4.14 (m, 2 H), 3.56-3.33 (m, 2 H), 2.98-2.95 (m, 2 H), 2.25 (s, 2 H), 2.21 (s, 3 H), 1.05 (s, 9 H).

[0318] Preparation Example 6: Synthesis of compound S-006

[0319] Step 1: Synthesis of intermediate 6-2

[0320] Compound 6-1 (1.00 g, 8.12 mmol) was dissolved in 10 mL of acetic acid, and 6-1a (1.20 g, 8.12 mmol) was added. The system was heated to 100°C under nitrogen, and stirred for 2 hours. LCMS monitoring showed that the raw material was consumed completely, and the product was generated. After the system was cooled to room temperature, it was diluted with 50 mL of water, stirred and filtered, the filter cake was dissolved with 25 mL of ethyl acetate, and sequentially washed with saturated sodium carbonate solution (15 mL x 2), water (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate 6-2 as a brown solid (1.43 g, yield: 69.54%). LCMS (ESI): m / z C 15 H 12 NO3 + [M+H] + Calcd = 254.08, Found = 254.1.

[0321] Step 2: Synthesis of intermediate 6-3

[0322] The intermediate 6-2 (1.43 g, 5.64 mmol) was dissolved in 14 mL of N,N-dimethylacetamide, and potassium carbonate (1.56 g, 11.28 mmol) and compound 6-2a (1.67 g, 8.46 mmol) were sequentially added. The reaction system was stirred at 120°C for 4 hours. LCMS monitoring showed that the raw material was consumed completely, and the product was generated. After the system was cooled to room temperature, it was diluted with 50 mL of water, and extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with water (15 mL x 2), saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:2 to 2:1) to obtain the intermediate 6-3 as a brown oil (1.4 g, yield: 67.19%). LCMS (ESI): m / z C 21 H 23 NNaO5 + [M+Na] + Calcd = 392.15, Found = 392.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.06-7.86 (m, 4 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.02 (dd, J = 19.9, 7.9 Hz, 2 H), 4.49 (t, J = 5.4 Hz, 1 H), 3.88 (d, J = 5.4 Hz, 2 H), 3.50-3.37 (m, 2 H), 3.30-3.16 (m, 2 H), 2.12 (s, 3 H), 0.88 (t, J = 7.0 Hz, 6 H); 13C NMR (101 MHz, DMSO-d6) δ ppm 167.36, 154.70, 138.89, 135.39, 132.04, 130.58, 124.02, 123.00, 120.20, 111.12, 100.04, 69.23, 62.48, 17.73, 15.44.

[0323] Step 3: Synthesis of intermediate 6-4

[0324] Intermediate 6-3 (2.80 g, 7.58 mmol) was dissolved in 28 mL of toluene and phosphoric acid (5.58 g, 48.4 mmol, 85% content) was added. The system was protected by nitrogen and stirred at 110 °C for 5 hours. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction liquid was filtered, the filter cake was washed with 50 mL of toluene, the organic phase was combined and concentrated under reduced pressure to a residue, which was purified by silica gel column chromatography (eluent: toluene) to give intermediate 6-4 as a light yellow solid (1.68 g, yield: 79.93%). 17 H 12 NO3 + [M+H] + Calculated = 278.08, Found = 278.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.12-7.95 (m, 4H), 7.92 (dd, J = 7.1, 2.7 Hz, 1H), 7.74-7.63 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 2.28 (d, J = 7.8 Hz, 3H); 13 C NMR (400 MHz, DMSO-d6) δ ppm 166.90, 151.06, 146.65, 135.72, 133.60, 131.88, 126.99, 125.94, 124.43, 122.61, 115.27, 107.66, 17.49.

[0325] Step 4: Synthesis of intermediate 6-5

[0326] Intermediate 6-4 (1.68 g, 6.06 mmol) was dissolved in 34 mL of methanol, and hydrazine hydrate (3.36 g, 33.6 mmol, 50% content) was added dropwise at 25 °C. The reaction system was stirred at 25 °C for 2 h. LCMS monitoring showed that the raw material was completely consumed and the product was generated. The reaction liquid was concentrated to a residue under reduced pressure, and 50 mL of water was added for dissolution. The mixture was extracted with ethyl acetate (25 mL x 2). The organic phase was washed with water (20 mL x 2), saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:5) to give intermediate 6-5 as a light yellow solid (600 mg, yield: 67.27%). LCMS (ESI): m / z C9H 10 NO + [M+H] + Calcd = 148.08, Found = 148.1.

[0327] Step 5: Synthesis of intermediate 6-6

[0328] Intermediate 6-5 (860 mg, 5.84 mmol) was dissolved in 8 mL of ethanol, and the system was cooled to -10 °C. N-bromosuccinimide (1.04 g, 5.84 mmol) was added in portions. The reaction system was stirred at -10 °C for 0.5 h. LCMS monitoring showed that the raw material was completely consumed. The system was quenched with 20 mL of saturated sodium sulfite solution, and extracted with ethyl acetate (10 mL x 3). The organic phase was combined, washed with water (10 mL x 2), saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:20) to give intermediate 6-6 as a light yellow oil (950 mg, yield: 71.95%). LCMS (ESI): m / z C9H9BrNO + [M+H] + Calcd = 225.99, 227.98, Found = 226.0, 228.0.

[0329] Step 6: Synthesis of intermediate 6-7

[0330] Intermediate 6-6 (900 mg, 3.98 mmol) was dissolved in 9 mL of dichloromethane, and diisopropylethylamine (2.52 g, 19.9 mmol) and compound 1-2a (1.08 g, 7.96 mmol) were added dropwise in turn. After the dropwise addition was completed, the system was stirred at 0 °C for 1 h. LCMS monitoring showed that the raw material was consumed completely and the product was generated. 5 mL of water was added to the system, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (3 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:5) to give intermediate 6-7 as a white solid (760 mg, yield: 58.9%). LCMS (ESI): m / z C 15 H 19 BrNO2 + [M+H]. [M+Na]. + Calcd = 324.06, 326.06, Found = 324.0, 326.0. 1 H NMR (400 MHz, CDC13) δ ppm 7.59 (d, J = 2.0 Hz, 1 H), 7.31 (s, 1 H), 6.94-6.84 (m, 1 H), 6.77 (d, J = 2.0 Hz, 1 H), 2.36 (s, 5 H), 1.18 (s, 9 H).

[0331] Step 7: Synthesis of compound S-006

[0332] Referring to the synthesis method of step 5 in Preparation Example 2, intermediate 6-7 was replaced with the corresponding raw material to prepare compound S-006 as a white solid. LCMS (ESI): m / z C 24 H 28 FN2O2 + [M+H]. [M+Na]. + Calcd = 395.21, Found = 395.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (s, 1 H), 7.85 (d, J = 2.1 Hz, 1 H), 7.37-7.20 (m, 1 H), 7.07-6.99 (m, 2 H), 6.98 (d, J = 2.1 Hz, 1 H), 6.63 (s, 1 H), 4.32 (s, 2 H), 3.48 (t, J = 5.7 Hz, 2 H), 3.03 (t, J = 5.6 Hz, 2 H), 2.23 (s, 5 H), 1.08 (s, 9 H).

[0333] Preparation Example 7: Synthesis of compound S-007

[0334] Step 1: Synthesis of intermediate 7-1

[0335] Intermediate 6-7 (390 mg, 1.2 mmol) was dissolved in 40 mL of ethanol, and 5% rhodium carbon Rh / C catalyst was added, the reaction system was replaced with nitrogen for three times, then replaced with hydrogen, and stirred at 25 °C under hydrogen atmosphere (1 MPa) for 6 hours. LCMS monitoring showed that the raw material was consumed completely, and the product was generated. The reaction solution was filtered through diatomite, the filtrate was concentrated to a residue under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:5) to obtain intermediate 7-1 as a white solid (195 mg, yield: 49.81%). LCMS (ESI): m / z C 15 H 21 BrNO2 + [M+H] + Calcd = 326.08, 328.07, Found = 326.1, 328.1. 1 H NMR (400 MHz, CDCl3) δ ppm 6.88 (s, 1H), 6.54 (s, 1H), 4.62 (t, J = 8.8 Hz, 2H), 3.21 (t, J = 8.7 Hz, 2H), 2.26 (s, 2H), 2.20 (s, 3H), 1.13 (s, 9H).

[0336] Step 2: synthesis of compound S-007

[0337] Referring to the synthesis method of step 5 in preparation example 2, replacing the corresponding raw material, intermediate 7-1 was used as the raw material to prepare compound S-007 as a white solid. LCMS (ESI): m / z C 24 H 30 FN2O2 + [M+H] + Calcd = 397.23, Found = 397.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (s, 1H), 7.31-7.12 (m, 1H), 7.03-6.91 (m, 2H), 6.35 (s, 1H), 4.47 (t, J = 8.5 Hz, 2H), 4.16 (s, 2H), 3.28 (t, J = 5.8 Hz, 2H), 3.15 (t, J = 8.5 Hz, 2H), 2.90 (t, J = 5.4 Hz, 2H), 2.12 (s, 2H), 2.07 (s, 3H), 1.03 (s, 9H).

[0338] Biological test example 1: patch clamp test of the effect of a compound on KCNQ2 / 3 potassium channel current

[0339] 1. Test purpose:

[0340] The effect of the compounds of the present application on the open activity of KCNQ2 / 3 channels was evaluated using a HEK-293 cell line stably expressing human KCNQ2 / 3 channels.

[0341] 2. Test method:

[0342] Cell culture: The HEK-293 cell line stably expressing human KCNQ2 / 3 channels (HEK-293 cells were obtained from ATCC) was cultured in DMEM medium containing 10% fetal bovine serum at 37°C with 5% CO2.

[0343] Cell passage: The old medium was removed and washed once with PBS, then 1 mL of 0.25% -Trypsin-EDTA solution was added, and incubated at 37°C for about 1 min. When the cells were detached from the dish bottom, about 5 mL of 37°C preheated complete medium was added. The cell suspension was gently blown with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube, and the cells were collected by centrifugation at 1000 rpm for 5 min. For expansion or maintenance culture, the cells were seeded in 6 cm cell culture dishes, and the amount of cells seeded in each cell culture dish was 2.5 x 10 5 cells (final volume: 5 mL).

[0344] Compound administration and patch clamp detection: Before patch clamp detection, the cells were separated by 0.25% -Trypsin-EDTA, and 8 x 10 3 cells were plated on a coverslip and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, administration and patch clamp detection were performed.

[0345] When the current amplitude of the cells in the control extracellular solution was stable, administration was started. The control extracellular solution and the working solution of the test compound (a suitable amount of the test substance was dissolved in DMSO and diluted to 0.2 mM, and then the test substance was diluted with the extracellular solution to prepare a working solution of 0.2 μM, which was ultrasonicated for 20 min without visible precipitate) flowed through the recording bath by gravity perfusion to act on the cells, and at the same time, liquid displacement was performed in the recording by using a peristaltic pump. All electrophysiological tests were performed at room temperature.

[0346] Extracellular solution: 140 mM NaCl, 5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 5 mM D-Glucose, 10 mM HEPES, pH = 7.4 with NaOH;

[0347] Intracellular fluid: 125mM K-Aspartic, 20mM KCl, 10mM EGTA, 1mM MgCl2·6H2O, 5mM Mg-ATP, 5mM HEPES, pH=7.2 with KOH;

[0348] The voltage stimulation protocol for whole-cell patch-clamp recording of KCNQ2 / 3 channel currents is as follows: After whole-cell occlusion, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -120 mV to +40 mV in 10 mV steps and maintained for 3 s. The mean steady-state current is used for IV curve analysis. Then, recording is continued at -30 mV for 500 ms, and the tail current peak is used for activation curve analysis.

[0349] 3. Data Analysis:

[0350] First, plot the IV curve with step voltage (Voltage) on the horizontal axis and normalized current (Normalized current) on the vertical axis. Then, compare the relative current magnitudes after compound action at -30mV voltage and calculate the increase factor of the current amplitude after compound action relative to the current amplitude without drug administration: Activation% = (Icompound / Icontrol) * 100%.

[0351] The activation curve is fitted by the peak tail current using the Boltzmann equation, i.e., I / Imax = 1 / (1 + exp((V)) 1 / 2 -Vm) / к)), where I / Imax is the normalized tail current magnitude, V 1 / 2 Vm is the test voltage, κ is the slope factor affecting the activation curve, and ΔV is the half-activation voltage. 1 / 2 =V 1 / 2 test-V 1 / 2 control formula (V) 1 / 2 test represents the half-activation voltage V after drug administration. 1 / 2 V 1 / 2 control represents V when the same cell is not drugged. 1 / 2 To calculate V for a given concentration of a compound. 1 / 2 Left shift magnitude.

[0352] 4. Experimental results: See Table 1 for details.

[0353] Table 1. Effects of compounds on KCNQ2 / 3 potassium channel current

[0354] The compounds of the present application have good KCNQ2 / 3 channel opening activity, and the half-activation voltage is significantly left-shifted, which is superior to XEN-1101 and S-004 compounds.

[0355] Biological test example 2: Patch clamp test of the effect of the compound on KCNQ4, KCNQ5 potassium current

[0356] 1. Purpose of the test:

[0357] The HEK293 cell line stably expressing human KCNQ4 or transiently expressing KCNQ5 channel was used to evaluate the effect of the compound of the present application on the opening activity of KCNQ4, KCNQ5 channel.

[0358] 2. Test method:

[0359] Culture and passage of HEK293 cells stably expressing KCNQ4: The HEK293 cell line stably expressing human KCNQ4 (NM_004700) channel was cultured in DMEM medium containing 10% fetal bovine serum, and the culture temperature was 37°C and the carbon dioxide concentration was 5%. Cell passage: remove the old culture medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution, incubate at 37°C for about 1 min. When the cells are detached from the dish bottom, add about 5 mL of 37°C preheated complete culture medium. The cell suspension is gently blown with a pipette to separate the aggregated cells. The cell suspension is transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, the cells are inoculated in 6 cm cell culture dishes, and the amount of cells inoculated in each cell culture dish is 2.5 x 10 5 cells (final volume: 5 mL). The cells were detached with 0.25%-Trypsin-EDTA before patch clamp test, and 7 x 10 3 cells were plated on coverslips and cultured in a 24-well plate (final volume: 500 μL), and drug administration and test detection were performed after 18 hours.

[0360] Culture and transfection of HEK293 cells transiently expressing KCNQ5 (NM_019842): HEK-293 cells were cultured in DMEM medium containing 10% fetal bovine serum, and the culture temperature was 37°C and the carbon dioxide concentration was 5%.

[0361] Day 1: inoculate cells into 6-well plates, 5 x 10 5 cells per well.

[0362] Day 2: use Invitrogen Lipofectamine TM3000 transfection reagent, the ratio of plasmid to transfection reagent is 1 μg:2 μL. The total amount of plasmid per well is 3 μg. Specifically as follows: take two sterile centrifuge tubes, each add 100 μL Opti-MEM TM , one of which adds 6 μL Lipofectamine 3000, mix well; the other tube adds 3 μg plasmid, mixes well, then adds 6 μL P3000 TM , mix well; then add the diluted plasmid DNA to the diluted Lipofectamine 3000, incubate at room temperature for 10-15 min. Add the DNA-liposome complex to the cells, mix gently, and place in the incubator. Change the liquid after 4-6 hours.

[0363] The third day: digest the cells, inoculate into the 24-well plate with pre-placed coverslips, 8x10 3 cells per well.

[0364] The fourth day: perform drug administration and patch clamp detection.

[0365] Compound administration and patch clamp detection: when the current amplitude of the cells in the control extracellular solution is stable, start drug administration. The control extracellular solution and the working solution of the test compound (dissolve an appropriate amount of the test substance in DMSO and dilute to 0.2 mM, then dilute the test substance in extracellular solution to prepare a 0.2 μM working solution, ultrasonic for 20 min, no visible precipitate) is used to flow through the recording bath to act on the cells by gravity perfusion, while liquid displacement is performed in the recording by using a peristaltic pump. All electrophysiological tests are performed at room temperature.

[0366] Extracellular solution: 140 mM NaCl, 5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 5 mM D-Glucose, 10 mM HEPES, pH=7.4 with NaOH;

[0367] Intracellular solution: 125 mM K-Aspartic, 20 mM KCl, 10 mM EGTA, 1 mM MgCl2·6H2O, 5 mM Mg-ATP, 5 mM HEPES, pH=7.2 with KOH;

[0368] The voltage stimulation scheme for recording KCNQ potassium current by whole-cell patch clamp is as follows: after forming a whole-cell seal, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -120 mV to +40 mV at 10 mV steps, maintained for 3 s, and the steady-state current mean value is used for IV curve analysis; then continuously record for 500 ms at a voltage of -30 mV, and the tail current peak is used for activation curve analysis.

[0369] 3. Data analysis:

[0370] First, the IV curve was plotted with the step voltage as the horizontal axis and the normalized current as the vertical axis, then the relative current size after the action of the compound at -30 mV was compared and the fold increase of the current amplitude after the action of the compound relative to the current amplitude without administration was calculated Activation% = (Icompound / Icontrol) * 100%.

[0371] The activation curve was fitted by the Boltzmann equation from the peak value of the tail current, that is, I / Imax = 1 / (1+exp((V 1 / 2 -Vm) / k)), where I / Imax is the normalized tail current amplitude, V 1 / 2 is the half-activation voltage, Vm is the test voltage, k is a related factor that affects the slope of the activation curve, and the left shift amplitude of the compound at a specified concentration is calculated using the formula V 1 / 2 = V 1 / 2 test-V 1 / 2 control. 1 / 2 test represents the half-activation voltage V 1 / 2 of the compound after administration, V 1 / 2 control represents V 1 / 2 of the same cell without administration. 1 / 2

[0372] 4. Test results: see Table 2.

[0373] Table 2. Effect of the compound on KCNQ4, KCNQ5 potassium channel current

[0374] Compared with XEN1101, the opening degree of the compound of the present application to KCNQ4 and KCNQ5 is low, and the selectivity to KCNQ2 / 3 is significantly improved, and the toxic side effects are expected to be small.

[0375] Biological test example 3: protective effect of the compound on a mouse epilepsy model induced by pentylenetetrazole (PTZ)

[0376] 1. Purpose of the test:

[0377] A male KM mouse seizure model induced by pentylenetetrazole (PTZ) was used to evaluate the protective effect of the compound of the present application on PTZ-induced seizures.

[0378] 2. Test animals: ​

[0379] Select 18-24g of male KM mice, and the animals are purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0380] 3. Test method:

[0381] Before the test, randomly group the animals according to the body weight, 6 in each group, according to the animal experiment “3R” principle, give 3 doses of 5mg / kg, if the proportion of V stage in 3 is more than 50%, it is considered that the protection effect is general, and no other animal is given, otherwise the remaining 3 mice continue to be given. At the beginning of the test, 5mg / kg of the test compound is given by gavage according to the body weight, the solvent: 10% DMSO+10%solutol+80% physiological saline, the concentration is 0.5mg / ml, the volume of the drug is 10ml / kg; 1h later, 80mg / kg of PTZ is injected subcutaneously to induce epilepsy, the injection volume is 10ml / kg, the concentration is 8mg / ml, the number of clonic and tonic seizures within 1h after PTZ injection is observed, and the time and death are observed; according to table 3, the proportion of V stage induced by PTZ after drug administration (V stage ratio % = V stage animal number / total number of test animals * 100) is used to evaluate the protective effect of the compound on PTZ-induced mouse epilepsy.

[0382] Table 3: Epilepsy grading

[0383] 4. Test results: see table 4.

[0384] Table 4: Effect of different compounds on the proportion of V stage induced by PTZ

[0385] The compound of the present application has a good protective effect on V stage epilepsy induced by PTZ in mice; the effect is significantly better than that of XEN-1101, S-004 and S-005.

[0386] Biological test example 4: effect of the compound on the motor balance and coordination ability of mice

[0387] 1. Test purpose:

[0388] The rotarod test is used to evaluate the effect of the compound of the present application on the motor balance and coordination ability of male KM mice.

[0389] 2. Test animals:

[0390] KM mice, 18-24g, purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0391] 3. Test method:

[0392] Pre-training was performed on all mice one day before the test. The rotarod fatigue instrument was set to rotate at 6 rpm, and only mice that remained on the rod for at least 1 minute each time in 3 consecutive tests (3 minutes) were left. In the formal test, the mice were weighed and randomly divided into groups according to their body weight, with 6 mice in each group. At the beginning of the test, 60 mg / kg of the test compound was administered by gavage, and the solvent: 10% DMSO + 10% solutol + 80% normal saline; the drug was administered by gavage according to the body weight of the mice, and the administration volume was 10 mL / kg.

[0393] The rotarod fatigue instrument was set to rotate at 6 rpm for 3 minutes. One hour after administration, the mice were placed on the rotating rod of the fatigue instrument in turn, and after observing that the mice could move smoothly on the rotating rod for at least 2 seconds, the Run button was clicked to start timing. The time for the mice to fall off the rod was recorded, and this was done for 3 consecutive times. If the mice did not fall off after 60 seconds, 60 seconds was counted as the time. The percentage of animals falling off the rotating rod (the number of animals falling off within 60 seconds / the number of test animals * 100%) was calculated.

[0394] 4. Test results: see Table 5.

[0395] Table 5. Effect of compounds on the motor balance and coordination of mice

[0396] The compounds of the present application had no significant effect on the motor balance and coordination of mice, and the safety window was better than that of XEN-1101.

[0397] Biological test example 5: Study of the absorption and blood-brain barrier penetration ability of the compounds

[0398] 1. Purpose of the test:

[0399] To evaluate the absorption and blood-brain barrier penetration ability of the compounds of the present application.

[0400] 2. Test animals:

[0401] KM mice, 18-24 g, purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0402] 3. Test method:

[0403] KM mice were administered by gavage with 5 mg / kg of the compounds of the present application according to their body weight, with 3 mice in each group, and the solvent: 10% DMSO + 10% solutol + 80% normal saline, and the administration volume was 10 ml / kg. At the 1 h time point after administration, at least 0.5 mL of whole blood was collected into an EDTA-K2 anticoagulant tube, and within half an hour, the blood plasma was obtained by centrifugation (6000 rpm, 8 minutes, 4°C), and was stored at -80°C for later use. At the same time, the brain tissue was collected, washed with normal saline, dried with absorbent paper, weighed, and stored at -80°C for later use.

[0404] The concentration of the compound in the plasma and brain tissue samples was analyzed by HPLC-MS / MS.

[0405] Test results: see Table 6.

[0406] Table 6. Brain-blood concentration of KM mice after a single oral administration of 1 h

[0407] The compound of the present application has good oral absorption and brain penetration ability, B / P>3, and the 1 h plasma and brain tissue concentrations are significantly higher than those of XEN-1101.

[0408] Biological test example 6: protective effect of the compound on the maximal electroshock (MES) induced convulsive seizure model in mice

[0409] 1. Purpose of the test:

[0410] The maximal electroshock model (MES model) was used to evaluate the protective effect of the compound of the present application on MES-induced convulsive seizures.

[0411] 2. Test animals:

[0412] Male KM mice weighing 18-25 g were selected, and the animals were purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0413] 3. Test method:

[0414] Before the test, the animals were randomly divided according to their body weight, with 6 animals in each group. At the beginning of the test, the animals were orally administered with a series of doses of the test compound (solvent preparation) according to their body weight, with a dosing volume of 10 mL / kg, and the solvent was 10% DMSO + 10% Solutol + 80% physiological saline. Six hours after administration, the auricular electrodes were moistened with physiological saline, clamped on the ears of the animals, and an electric shock was applied using an electric shock instrument (60 Hz, 0.3 ms, 1 s, 45 mA). The occurrence of convulsive seizures in the animals was observed and recorded, and the protective effect of the compound on MES-induced convulsive seizures in mice was evaluated by the protection rate of MES-induced convulsive seizures after administration. The convulsive seizure protection rate (%) = (1- the number of animals with convulsive seizures / the number of test animals) * 100. The ED 50 .

[0415] 4. Test results: see Table 7.

[0416] Table 7. Protective effect of different compounds on MES-induced convulsive seizures in mice

[0417] The compound has good protection effect on MES-induced convulsive seizures of mice, and the effect is significantly better than that of XEN-1101.

Claims

A compound of Formula V or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, 5, or 6; each R 1 each independently D, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or substituted C1-C6alkyl; 1-1 substituted C1-C6alkyl; each R 1A each independently D, -OH, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or substituted C1-C6alkyl; 1-1 substituted C1-C6alkyl; each R 1-1 each independently D or halogen; R 2 is methyl or methyl substituted with 1-3 D; R' is H or D; R 3 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R 3-1 substituted C3-C8cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-2 substituted C1-C6alkyl; each R 3-1 each independently D, halogen, or Ci-C6alkyl; each R 3-2 each independently D or halogen; X and Z are each independently O, S, CR 4 or C(R 4 )2; Y is N, C(R 5 )2 or CR 5 ; each R 4 and each R 5 each independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 substituted C1-C6alkyl; each R 4-1 each independently D or halogen; or, R 4 and R 5 with the carbon atom to which they are directly attached form a three-membered saturated carbocyclic ring, which can be optionally substituted with one or more R 4-2 each R 4-2 is independently D or halogen; is a single or double bond, and two of (X and Y between with Y and Z between are not both double bonds; When one of X and Z are each independently O, S, CR 4 or C(R 4 )2; Y is N or CR 5 ; and when X and Z are both CR 4 or C(R 4 )2(i.e., X is CR 4 , Z is C(R 4 )2, or X is C(R 4 )2, Z is CR 4 ), Y is not N; wherein each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen; When two are both single bonds, it is case (1) or (2): Case (1): X is O or S; Y is C(R 5 )2; Z is C(R 4 )2; wherein each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen; Case (2): One of X and Z is O or S; the other is CHR 4 ; Y is CHR 5 ; wherein R 4 and R 5 together with the carbon atom to which they are directly attached form a three-membered saturated carbocyclic ring, which can be optionally substituted with one or more R 4-2 , each R 4-2 is independently D or halogen. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein The compound is a compound of formula I: wherein n is 0, 1, 2, or 3; each R 1 each independently D, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or substituted C1-C6alkyl; 1-1 substituted C1-C6alkyl; each R 1-1 each independently D or halogen; R 2 is methyl or methyl substituted with 1-3 D; R 3 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R 3-1 substituted C3-C8cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-2 substituted C3-C8cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R each R 3-1 each independently D, halogen, or Ci-C6alkyl; each R 3-2 each independently D or halogen; X and Z are each independently O, S, CR 4 or C(R 4 )2; Y is N, C(R 5 )2 or CR 5 ; each R 4 and each R 5 is each independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 is each independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 is each independently D or halogen; or R 4 and R 5 together with the carbon atom to which they are directly attached form a three-membered saturated carbocyclic ring, which can be optionally substituted with one or more R 4-2 each R 4-2 is independently D or halogen; is a single or double bond, and two of (X and Y between with Y and Z between are not both double bonds; When one of X and Z are each independently O, S, CR 4 or C(R 4 )2; Y is N or CR 5 , and when X, Z are both CR 4 or C(R 4 )2 (i.e., X is CR 4 , Z is C(R 4 )2, or X is C(R 4 )2, Z is CR 4 ), Y is not N; wherein each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen; When two are both single bonds, it is case (1) or (2): Case (1): X is O or S; Y is C(R 5 )2; Z is C(R 4 )2; wherein each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen; Case (2): One of X and Z is O or S; the other is CHR 4 ; Y is CHR 5 ; wherein R 4 and R 5 together with the carbon atom to which they are directly attached form a three-membered saturated carbocyclic ring, which can be optionally substituted with one or more R 4-2 , each R 4-2 is independently D or halogen. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 or 2, wherein which satisfy one or more of the following conditions: (1) R 1 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (2) R 1 C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl, and C1-C6alkyl in C1-C6alkyl substituted by one or more R 1-1 each independently is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, preferably methyl; (3) R 1A In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (4)R 1A In the context of C1-C6 alkyl, -O-C1-C6 alkyl, and C1-C6 alkyl and R 1-1 The C1-C6 alkyl groups that are substituted are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, preferably methyl; (5) R 1-1 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (6) R 2 In one embodiment, the methyl group substituted with 1-3 D is a methyl group substituted with 1, 2, or 3 D. (7) R 3 C1-C6alkyl, C1-C6alkyl in -Si(C1-C6alkyl)3, and C1-C6alkyl in C1-C6alkyl substituted by one or more R 3-2 each independently of one another H, C1-C6alkyl, C1-C6alkyl substituted by one or more R each independently of one another H, C1-C6alkyl, C1-C6alkyl substituted by one or more R (8) R 3 C3-C8cycloalkyl and C3-C8cycloalkyl substituted by one or more R 3-1 each independently of one another, C3-C6monocyclic cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably cyclopropyl; (9) R 3-1 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (10) R 3-1 In particular, the C1-C6alkyl group is a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl group, preferably a methyl group. (11) R 3-2 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (12) R 4 and R 5 each independently is selected from the group consisting of hydrogen, halogen, -CN, -NO2, -OH, -SF5, -NH2, -SCF3, -C1-C6alkyl, -O-C1-C6alkyl, -C1-C6alkyl substituted by one or more R 4-1 each independently is selected from the group consisting of hydrogen, halogen, -CN, -NO2, -OH, -SF5, -NH2, -SCF3, -C1-C6alkyl, -O-C1-C6alkyl, -C1-C6alkyl substituted by one or more R (13) R 4 and R 5 wherein said halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (14) R 4-1 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (15) R 4-2 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; and (16) said one or more means 1, 2, 3, 4, 5, 6, 7, 8, or 9, preferably 1, 2, 3, or 4, more preferably 1 or 2. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein which satisfy one or more of the following conditions: (1) n is 0 or 1; (2) m is 0, 1, 2, 4, or 6; (3) each R 1 each independently halogen, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogen; (4) each R 1A each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen; (5) R 2 is methyl or methyl substituted with 3 D; (6) R' is H; (7) R 3 C1-C6 alkyl, C3-C6 monocyclic cycloalkyl substituted by one or more R 3-1 C3-C6 monocyclic cycloalkyl substituted by one or more R 3-2 C1-C6 alkyl, -Si(C1-C6 alkyl)3, or C3-C6 monocyclic cycloalkyl substituted by one or more R 3-1 C1-C6 alkyl, -Si(C1-C6 alkyl)3, or C3-C6 monocyclic cycloalkyl substituted by one or more R (8) each R 3-1 each independently C1-C6alkyl, preferably methyl; (9) each R 3-2 each independently D or fluoro, preferably D; (10) when one of when the double bond is in (E) form, For wherein X is CR 4 ; Y is N or CR 5 ; Z is O, S, or C(R 4 )2; and when X is CR 4 and Z is C(R 4 )2, Y is not N; each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen; or When one of when the double bond is in (E) form, For wherein X is O, S, or C(R 4 )2; Y is N or CR 5 ; Z is CR 4 ; and when X is C(R 4 )2and Z is CR 4 , Y is not N; each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen; or When two are each a single bond, For wherein X is O or S; Y is C(R 5 )2; Z is C(R 4 )2; each R 4 and each R 5 is independently H, D, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 4-1 ; each R 4-1 is independently D or halogen; or When two are each a single bond, For X and Z are each independently O or S; o is 0, 1, 2, 3 or 4, preferably 0 or 2; each R 4-2 each independently D or halogen, preferably D or fluorine; wherein ring forms a fused ring with the phenyl group through this bond; (11) each R 4 each independently H, D, fluoro, or methyl; (12) each R 5 each independently H, D, fluoro, or methyl; (13) each R 4-1 each independently D or fluoro; (14) each R 4-2 each independently D or fluoro; (15) For wherein n is 0, 1, 2, or 3, each R 1 each independently D, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogen; m is 0, 1, 2, 3, 4, 5, or 6 (preferably 0, 2, 4, or 6), each R 1A each independently D, -OH, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogen (preferably, R 1 is halogen (e.g., fluorine), R 1A is D or -OH); and (16) For wherein n is 0 or 1, each R 1 each independently D, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogen. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein which satisfy one or more of the following conditions: (1) n is 1; (2) m is 0, 2, 4, or 6; (3) each R 1 each independently halogen; preferably fluorine; (4) each R 1A each independently D or -OH; (5) R 2 is methyl; (6) R 3 is tert-butyl, ethyl, preferably tert-butyl, ethyl, Further preferred is tert-butyl or more preferably tert-butyl; (7) R 3-1 is methyl; (8) R 3-2 is D; (9) For wherein o is 0, 1, 2, 3 or 4, preferably 0 or 2; Preferably (10) each R 4 each independently H or D; (11) each R 5 each independently H or D; (12) each R 4-1 each independently D; and (13) each R 4-2 each independently D. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein The compound is a compound as shown in Formula V-1, Formula V-2, Formula V-3, Formula V-4, or Formula V-5: wherein Z is O, S or C(R 4 )2; X is O, S or C(R 4 )2; X' is O or S; o is 0, 1, 2, 3 or 4; n, m, R 1 , R 1A , R 2 , R', R 3 , R 4 , R 5 and R 4-2 are as defined in any one of claims 1-5; Preferably, the compound is according to any one of the following: (1) in a compound according to Formula V-1, n is 0 or 1, preferably 1; m is 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, 4, or 6; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen, preferably halogen (e.g., fluorine); each R 1A each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens, preferably D or -OH; R 2 is methyl or methyl substituted by 1-3 D, preferably methyl; R' is H or D, preferably H; R 3 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-1 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-2 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-2 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R each R 3-1 each independently is C1-C3alkyl, preferably methyl; each R 3-2 each independently D or fluoro, preferably D; Z is O, S or C(R 4 )2; each R 4 each independently H, D, halogen, or Ci-C6alkyl; R 5 H, D, halogen or Ci-C6alkyl; (2) in a compound according to Formula V-2, n is 0 or 1, preferably 1; m is 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, 4, or 6; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen, preferably halogen (e.g., fluorine); each R 1A each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens, preferably D or -OH; R 2 is methyl or methyl substituted by 1-3 D, preferably methyl; R' is H or D, preferably H; R 3 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-1 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-2 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R 3-2 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted by one or more R each R 3-1 each independently is C1-C3alkyl, preferably methyl; each R 3-2 each independently D or fluorine, preferably D; X is O, S or C(R 4 )2; each R 4 each independently H, D, halogen, or Ci-C6alkyl; R 5 H, D, halogen or Ci-C6alkyl; (3) in a compound according to Formula V-3, n is 0 or 1, preferably 1; m is 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, 4, or 6; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens, preferably halogen (e.g., fluorine); each R 1A each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens, preferably D or -OH; R 2 is methyl or methyl substituted by 1-3 D, preferably methyl; R' is H or D, preferably H; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C6 monocyclic cycloalkyl, -Si(C1-C6 alkyl)3, or substituted with one or more R 3-2 Substituted C1-C6 alkyl groups, preferably C1-C6 alkyl groups or substituted with one or more R groups. 3-2 The substituted C1-C6 alkyl group is more preferably a C1-C6 alkyl group; each R 3-1 each independently is C1-C3alkyl, preferably methyl; each R 3-2 each independently D or fluorine, preferably D; X' is O or S; each R 4 each independently H, D, halogen, or Ci-C6alkyl; each R 5 each independently H, D, halogen, or Ci-C6alkyl; (4) in a compound according to Formula V-4 and V-5, n is 0 or 1, preferably 1; m is 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, 4, or 6; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen, preferably halogen (e.g., fluorine); each R 1A each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens, preferably D or -OH; R 2 is methyl or methyl substituted by 1-3 D, preferably methyl; R' is H or D, preferably H; R 3 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted with one or more R 3-1 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted with one or more R 3-2 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted with one or more R 3-2 C3-C6monocyclic cycloalkyl, -Si(C1-C6alkyl)3, or C1-C6alkyl substituted with one or more R each R 3-1 each independently is C1-C3alkyl, preferably methyl; each R 3-2 each independently D or fluorine, preferably D; o is 0, 1, 2, 3, or 4, preferably 0 or 2; each R 4-2 each independently D or halogen, preferably D or F. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein The compound is a compound of Formula I-1, Formula I-2, Formula I-3, Formula I-4, or Formula I-5: wherein Z is O, S or C(R 4 )2; X is O, S or C(R 4 )2; X' is O or S; o is 0, 1, 2, 3 or 4; n, R 1 , R 2 , R 3 , R 4 , R 5 and R 4-2 are as defined in any one of claims 1-5; Preferably, the compound is according to any one of the following: (1) in a compound according to Formula I-1, n is 0 or 1; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; R 2 is methyl or methyl substituted with 1-3 D; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C6 monocyclic cycloalkyl or -Si(C1-C6 alkyl)3; each R 3-1 each independently is C1-C3alkyl, preferably methyl; Z is O, S or C(R 4 )2; each R 4 each independently H, D, halogen, or Ci-C6alkyl; R 5 H, D, halogen or Ci-C6alkyl; (2) in a compound according to Formula I-2, n is 0 or 1; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; R 2 is methyl or methyl substituted with 1-3 D; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C6 monocyclic cycloalkyl or -Si(C1-C6 alkyl)3; each R 3-1 each independently is C1-C3alkyl, preferably methyl; X is O, S or C(R 4 )2; each R 4 each independently H, D, halogen, or Ci-C6alkyl; R 5 H, D, halogen or Ci-C6alkyl; (3) in a compound according to Formula I-3, n is 0 or 1; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; R 2 is methyl or methyl substituted with 1-3 D; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C6 monocyclic cycloalkyl or -Si(C1-C6 alkyl)3; each R 3-1 each independently is C1-C3alkyl, preferably methyl; X' is O or S; each R 4 each independently H, D, halogen, or Ci-C6alkyl; each R 5 each independently H, D, halogen, or Ci-C6alkyl; (4) in a compound according to Formula I-4 and I-5, n is 0 or 1; R 1 halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; R 2 is methyl or methyl substituted with 1-3 D; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C6 monocyclic cycloalkyl or -Si(C1-C6 alkyl)3; each R 3-1 each independently is C1-C3alkyl, preferably methyl; o is 0, 1, 2, 3, or 4, preferably 0 or 2; each R 4-2 each independently D or halogen, preferably D or F; Further preferably, the compound is according to any one of the following: (1) in a compound according to Formula I-1, n is 1; R 1 is halogen; preferably F; R 2 is methyl; R 3 is tert-butyl, preferably tert-butyl; Z is O or CH2; R 4 is H or D; R 5 is H or D; (2) in a compound according to Formula I-2, n is 1; R 1 is halogen; preferably F; R 2 is methyl; R 3 is tert-butyl, preferably tert-butyl; X is O or CH2; R 4 is H or D; R 5 is H or D; (3) in a compound according to Formula I-3, n is 1; R 1 is halogen; preferably F; R 2 is methyl; R 3 is tert-butyl, preferably tert-butyl; X' is O; R 4 is H or D; R 5 is H or D; (4) in a compound according to Formula I-4 and I-5, n is 1; R 1 is halogen; preferably F; R 2 is methyl; R 3 is tert-butyl, preferably tert-butyl; o is 0. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein which satisfy one or more of the following conditions: (1) For Preferably (2) For and (3) For The compound or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein The compound is any one of the following compounds: A compound of Formula III, wherein R 2 , R', R 3 , X, Y and Z are as defined in any one of claims 1-9; Preferably, the compound is a compound of formula III, wherein R 2 , R 3 , X, Y and Z are as defined in any one of claims 1-9. Further preferably, the compound is any one of the following structures: A process for the preparation of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, comprising the step of coupling a compound according to formula II’ or a salt thereof and a compound according to formula III’ in a solvent, preferably in the presence of a catalyst, preferably a Pd catalyst, and a base, to give a compound according to formula V, as shown below; wherein n, R 1 , R 2 , R', R 3 , X, Y and Z are as defined in any one of claims 1-9; Preferably, the preparation method comprises the following step: carrying out a coupling reaction as shown below on a compound as shown in formula II or a salt thereof and a compound as shown in formula III in a solvent, preferably in the presence of a catalyst (preferably a Pd catalyst) and a base, to obtain a compound as shown in formula I; wherein n, R 1 , R 2 , R 3 , X, Y and Z are as defined in any one of claims 1-9. A pharmaceutical composition, characterized by The pharmaceutical composition comprises: (1) a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a compound prepared according to the method of claim 11, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable excipient. Use of a compound as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, a compound produced by the method of claim 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12, wherein The application is the use as a KCNQ2 / 3 channel opener, or the use in the manufacture of a medicament for the prevention or treatment of a disease; Preferably, the disease is a KCNQ2 / 3 channel related disease; Further preferably, the KCNQ2 / 3 channel related disease is epilepsy, depression, anxiety or pain; more preferably focal seizures or generalized tonic-clonic seizures.

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