Compound containing aromatic fused ring, pharmaceutical composition thereof and use thereof

Abstract

Provided are a compound containing an aromatic fused ring, a pharmaceutical composition thereof and the use thereof. Specifically provided is compound I' or a pharmaceutically acceptable salt thereof, which has one or more of the following effect advantages: (1) a novel structure; (2) a good KCNQ2 / 3 channel opening effect; (3) a relatively weak KCNQ4 and KCNQ5 opening activity; (4) a good KCNQ2 / 3 selectivity; (5) low toxic side effects; (6) a good in-vivo efficacy with a good anti-seizure effect; (7) an excellent safety window; (8) a good brain-to-blood ratio; and (9) good concentrations in the brain and the blood.

Description

A compound containing an aromatic fused ring, a pharmaceutical composition thereof and application

[0001] This application claims priority to Chinese Patent Application No. 2024110646432, filed on August 2, 2024, and Chinese Patent Application No. 2025110246523, filed on July 23, 2025. This application incorporates the entirety of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to a compound containing an aromatic fused ring, a pharmaceutical composition thereof and application. BACKGROUND

[0003] The voltage-gated potassium ion channel Kv7 family is encoded by the KCNQ gene and plays an important role in regulating neuronal excitability and maintaining normal neural rhythm. Currently, the Kv7 channels found include five subtypes (Kv7.1-Kv7.5), which are encoded by KCNQ1-KCNQ5 genes, respectively, and KCNQ2-KCNQ5 are expressed in the central nervous system except KCNQ1 mainly expressed in myocardium. Among them, Kv7.2 and Kv7.3 encoded by KCNQ2 and KCNQ3 can form homomeric or heteromeric tetramers, which are the main molecular basis of forming neuronal M current. The opening of this channel can make potassium ions outflow, reduce neuronal excitability, and inhibit neuronal repetitive and sustained discharge. KCNQ2 / 3 gene mutation or functional reduction can lead to reduced potassium ion outflow, triggering neurological hyperexcitability-related diseases including epilepsy, neuropathic pain, etc. Therefore, the Kv7.2 / 3 channel opener becomes a new strategy for clinical treatment of hyperexcitability-related diseases such as seizures, anxiety and pain. KCNQ4 is mainly expressed in the cochlea and vestibular organs of the inner ear and the central auditory transmission pathway. It has been confirmed that KCNQ4 gene mutation can cause hereditary deafness. Recent studies have also found that KCNQ4 is expressed in skeletal muscle, internal organs and vascular smooth muscle; KCNQ5 is expressed in the brain and vascular smooth muscle, so affecting the opening of Kv7.4 and Kv7.5 channels may have related side effects on hearing, muscle contraction and other functions, thereby limiting clinical application.

[0004] The first generation drug retigabine (RTG) as an adjunct therapy for adult epilepsy partial seizures, was approved by the US FDA in 2011. However, due to the weak activity of retigabine on KCNQ2 / 3 potassium channel opening, the clinical use dose reaches 1.2 grams / day, and it has strong agonistic activity on KCNQ4, KCNQ5 and other potassium channels, and the selectivity of KCNQ2 / 3 is not good, which increases the probability of peripheral side effects. In addition, its structure contains a triamine benzene structure, and the chemical stability of the drug itself is not good, and it is easy to dimerize, which can cause serious skin, retinal tissue pigmentation. The new generation of KCNQ agonists, such as HN37 and XEN-1101, are currently in the clinical stage. These compounds have significantly improved activity compared to retigabine, but the types are single and there is still room for improvement. SUMMARY

[0005] The present application provides a novel structure of a compound containing an aromatic fused ring, a pharmaceutical composition thereof and application. Specifically, a compound I' (compound of formula I') or a pharmaceutically acceptable salt thereof,

[0006] wherein,

[0007] n' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0008] each R 1 is independently D, -OH, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl or C1-C6alkyl substituted with one or more halogens;

[0009] Ring A is wherein represents that ring A is formed with the bond and the phenyl ring;

[0010] p is 1 or 2;

[0011] q is 0, 1, 2, 3, 4, 5 or 6;

[0012] each R 2 is independently D, -OH, halogen, C1-C6alkyl, -O-C1-C6alkyl or C1-C6alkyl substituted with one or more R 2-1 ;

[0013] Alternatively, two R 2 on adjacent carbons, together with the carbon atoms to which they are directly attached, form a three-membered saturated carbocyclic ring, which can be optionally substituted with 1 or 2 R 2-2 ;

[0014] each R2-1 Each is independently either D or halogen;

[0015] Each R 2-2 Each is independently either D or halogen;

[0016] L' represents a chemical bond, -O-, or -(CR). L 2) m -;

[0017] Each R L Each can be H or D independently;

[0018] m is 1 or 2;

[0019] R 3 It is a C1-C6 alkyl, C3-C8 cycloalkyl, or formed by one or more R 3-1 Substituted C3-C8 cycloalkyl, -Si(C1-C6 alkyl)3, or substituted with one or more R 3-2 Substituted C1-C6 alkyl groups;

[0020] Each R 3-1 Each is independently D, halogen, C1-C6 alkyl, or -Si(C1-C6 alkyl)3;

[0021] Each R 3-2 Each is independently either D or halogen;

[0022] R 4 It is a methyl group or a methyl group substituted with 1-3 D atoms.

[0023] In some embodiments, compound I' is compound I.

[0024] This invention also provides a novel aromatic fused-ring compound, its pharmaceutical composition, and its application. Specifically, it is a compound I (compound of formula I) or a pharmaceutically acceptable salt thereof.

[0025] in,

[0026] n is 0, 1, 2, or 3;

[0027] Each R 1 Each is independently D, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or a C1-C6 alkyl substituted with one or more halogens;

[0028] Ring A is in This indicates that ring A forms a cyclic ring with the phenyl group through this bond;

[0029] p is 1 or 2;

[0030] q is 0, 1, 2, 3, 4, 5, or 6;

[0031] each R 2 are each independently D, -OH, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 2-1 substituted C1-C6 alkyl;

[0032] or two R 2 on adjacent carbons, together with the carbon atoms to which they are directly attached, form a three-membered saturated carbocyclic ring, which can be optionally substituted with 1 or 2 R 2-2 substituted;

[0033] each R 2-1 are each independently D or halogen;

[0034] each R 2-2 are each independently D or halogen;

[0035] L is a bond, -O-, or -(CH2) m -;

[0036] m is 1 or 2;

[0037] R 3 is C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more R 3-1 substituted C3-C8 cycloalkyl, -Si(C1-C6 alkyl)3, or C1-C6 alkyl substituted with one or more R 3-2 substituted C1-C6 alkyl;

[0038] each R 3-1 are each independently D, halogen, C1-C6 alkyl, or -Si(C1-C6 alkyl)3;

[0039] each R 3-2 are each independently D or halogen;

[0040] R 4 is methyl or methyl substituted with 1-3 D.

[0041] In the compounds of the present application, or their pharmaceutically acceptable salts, certain groups are defined as follows, and the definition of groups not mentioned is as described in any of the aspects of the present application (hereinafter referred to as "in some embodiments").

[0042] In some embodiments, R 1 independently fluorine, chlorine, bromine, or iodine; preferably fluorine.

[0043] In some embodiments, R 1In this embodiment, the halogen and the halogen in the C1-C6 alkyl group substituted with one or more halogens are each independently fluorine, chlorine, bromine or iodine; preferably fluorine.

[0044] In some implementation schemes, R 1 In the ', the C1-C6 alkyl group, the C1-C6 alkyl group in the -O-C1-C6 alkyl group, and the C1-C6 alkyl group in the C1-C6 alkyl group substituted with one or more halogens are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably methyl.

[0045] In some implementation schemes, R 1 In this context, the C1-C6 alkyl group, the C1-C6 alkyl group in the -O-C1-C6 alkyl group, and the C1-C6 alkyl group substituted with one or more halogens are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably methyl.

[0046] In some implementation schemes, R 2 In this context, the halogen is fluorine, chlorine, bromine, or iodine; preferably fluorine.

[0047] In some implementation schemes, R 2 In this context, the C1-C6 alkyl group, the C1-C6 alkyl group in the -O-C1-C6 alkyl group, and the C1-C6 alkyl group being formed by one or more R 2- 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.

[0048] In some implementation schemes, R 2-1 In this context, the halogen is fluorine, chlorine, bromine, or iodine; preferably fluorine.

[0049] In some implementation schemes, R 2-2 In this context, the halogen is fluorine, chlorine, bromine, or iodine; preferably fluorine.

[0050] In some implementation schemes, R 3 In the context, the C1-C6 alkyl group, with one or more R 3-2 The C1-C6 alkyl group in the substituted C1-C6 alkyl group and the C1-C6 alkyl group in -Si(C1-C6 alkyl)3 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl, ethyl or tert-butyl.

[0051] In some implementation schemes, R 3 In the case of the C3-C8 cycloalkyl group and one or more R 3-1C3-C8cycloalkyl in substituted C3-C8cycloalkyl is each independently C3-C6monocyclic cycloalkyl; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably cyclopropyl.

[0052] In some embodiments, R 3-1 In some embodiments, the halogen in the halogen, halo-Ci-C6alkyl, and halo-Ci-C6alkoxy is fluorine, chlorine, bromine or iodine; preferably fluorine.

[0053] In some embodiments, R 3-1 In some embodiments, the Ci-C6alkyl in the Ci-C6alkyl and -Si(Ci-C6alkyl)3 is each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl; preferably methyl.

[0054] In some embodiments, R 3-2 In some embodiments, the halogen in the halogen, halo-Ci-C6alkyl, and halo-Ci-C6alkoxy is fluorine, chlorine, bromine or iodine; preferably fluorine.

[0055] In some embodiments, R 4 In some embodiments, the methyl substituted with 1-3 D means methyl substituted with 1, 2 or 3 D.

[0056] In some embodiments, R 1-1 and R 1-2 In some embodiments, the halogen in the halogen, halo-Ci-C6alkyl, and halo-Ci-C6alkoxy is fluorine, chlorine, bromine or iodine; preferably fluorine.

[0057] In some embodiments, R 1-1 and R 1-2 In some embodiments, the Ci-C6alkyl in the Ci-C6alkyl, -O-Ci-C6alkyl, and Ci-C6alkyl substituted with one or more halogen is each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl; preferably methyl.

[0058] In some embodiments, in formula I', the one or more means 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0059] In some embodiments, in formula I, the one or more means 1, 2, 3 or 4; preferably 1 or 2.

[0060] In some embodiments, n' is 0, 1, 2, 3, 4, 5, 6 or 7; preferably 0, 1, 3, 5 or 7.

[0061] In some embodiments, n is 0 or 1; preferably 1.

[0062] In some embodiments, each R 1each independently D, -OH, halogen, -0-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen; preferably each R 1 each independently D, -OH, or halogen (e.g., F).

[0063] In some embodiments, each R 1 independently halogen, -0-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen; preferably each R 1 each independently halogen; more preferably fluorine.

[0064] In some embodiments, ring A is o is 0, 1, or 2; each R 2 each independently D, -OH, halogen, Ci-C6alkyl, -0-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 2-1 each independently D, -OH, halogen, Ci-C6alkyl, -0-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 2-2 each independently D or halogen; q is 0, 1, 2, 3, 4, 5, or 6;

[0065] preferably o is 0, 1, or 2; each R 2 each independently D, -OH, or halogen; each R 2-2 each independently D or halogen (e.g., fluorine); q is 0, 1, 2, 3, 4, 5, or 6 (e.g., q is 0, 1, or 2); more preferably each R 2 each independently -OH or fluorine; q is 0, 1, 2, 3, 4, 5, or 6 (e.g., q is 0, 1, or 2); further more preferably ring A is (e.g., ), (e.g., ), (e.g., (e.g., ),

[0066] In some embodiments, ring A is o is 0, 1, or 2; each R 2 each independently D, -OH, halogen, Ci-C6alkyl, -0-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 2-1 each independently D, -OH, halogen, Ci-C6alkyl, -0-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R o is 0, 1, or 2; each R 2 each independently D, -OH, or halogen; more preferably each R2 each independently -OH or fluorine; further more preferably, ring A is (e.g. ), (e.g. ), (e.g. ), (e.g. ),

[0067] In some embodiments, q is 0, 1, or 2; preferably 0 or 1.

[0068] In some embodiments, each R 2-1 each independently halogen; preferably fluorine.

[0069] In some embodiments, each R 2-2 each independently halogen; preferably fluorine.

[0070] In some embodiments, L’ is -O- or -(CR L 2) m ; each R L each independently H or D; m is 1 or 2.

[0071] In some embodiments, L’ is -O-, -(CH2) m - or -(CD2) m -; m is 1 or 2; preferably, L’ is -O-, -CH2- or -CD2-.

[0072] In some embodiments, L is -O- or -(CH2) m -; m is 1 or 2; preferably -CH2-.

[0073] In some embodiments, R 3 is C1-C6 alkyl, C3-C8 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 .

[0074] In some embodiments, R 3 is C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R 3-1 , or -Si(C1-C6 alkyl)3; preferably C1-C6 alkyl or C3-C8 monocyclic cycloalkyl substituted with one or more R 3-1 ; more preferably C1-C6 alkyl.

[0075] In some embodiments, R 3is methyl or methyl substituted with 3 D; preferably methyl. is methyl or methyl substituted with 3 D; preferably methyl.

[0076] In some embodiments, each R 3 is methyl or methyl substituted with 3 D; preferably methyl. is methyl or methyl substituted with 3 D; preferably methyl.

[0077] In some embodiments, each R 3-1 is each independently C1-C6 alkyl; preferably C1-C3 alkyl; more preferably methyl.

[0078] In some embodiments, each R 3-2 is each independently D or halogen.

[0079] In some embodiments, each R 3-2 is each independently halogen; preferably fluorine.

[0080] In some embodiments, R 4 is methyl or methyl substituted with 3 D; preferably methyl.

[0081] In some embodiments, is wherein n is 0, 1, 2, or 3, each R 1 is each independently D, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogen; k is 0, 1, 2, or 3 (preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2 is each independently D, -OH, -CN, halogen (e.g., fluorine), C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogen (preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH).

[0082] In some embodiments, is wherein n is 0, 1, 2, or 3, each R 1 is each independently D, halogen, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogen; k is 0, 1, 2, or 3 (preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2each independently D, -OH, halogen (e.g. fluorine), -0-Ci-C6alkyl or Ci-C6alkyl substituted with one or more halogen; 1-1 is halogen (e.g. fluorine), R 1-2 is D or -OH).

[0083] In some embodiments, is wherein n is 0 or 1 ; R 1 each is D, -CN, halogen, Ci-C6alkyl, -0-Ci-C6alkyl or Ci-C6alkyl substituted with one or more halogen.

[0084] In some embodiments, the compound I' is compound I-1 ', I-2', I-3' or I-4':

[0085] wherein o is 0, 1 or 2, n', R 1 ', R 2 , q, R 2-2 , L', R 3 and R 4 are as defined above.

[0086] In some embodiments, in compounds I-1'and I-2',

[0087] n' is 0, 1, 2, 3, 4, 5, 6 or 7;

[0088] each R 1 is independently D, -OH, halogen, -0-Ci-C6alkyl or Ci-C6alkyl substituted with one or more halogen;

[0089] q is 0, 1 or 2;

[0090] each R 2 is independently D, -OH or halogen;

[0091] L' is -0-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0092] R 3 is Ci-C6alkyl, C3-C8cycloalkyl substituted with one or more R 3-1 , -Si(Ci-C6alkyl)3 or Ci-C6alkyl substituted with one or more R 3-2 ;

[0093] R 3-1 is Ci-C3alkyl;

[0094] R3-2 is D or halogen;

[0095] R 4 is methyl or methyl substituted with 1-3 D.

[0096] In some embodiments, in compounds I-1’ and I-2’,

[0097] is

[0098] n is 0, 1, 2, or 3,

[0099] each R 1 is independently D, halogen, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogen;

[0100] k is 0, 1, 2, or 3 (more preferably, k is 0);

[0101] t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6);

[0102] each R 1-1 and R 1-2 is independently D, -OH, halogen (e.g., fluorine), -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogen (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH);

[0103] q is 0, 1, or 2;

[0104] each R 2 is independently D, -OH, or halogen;

[0105] L’ is -O-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0106] R 3 is C1-C6alkyl, C3-C8cycloalkyl substituted with one or more R 3-1 , -Si(C1-C6alkyl)3, or C1-C6alkyl substituted with one or more R 3-2 ;

[0107] R 3-1 is C1-C3alkyl;

[0108] R 3-2 is D or halogen;

[0109] R 4is methyl or methyl substituted with 1-3 D.

[0110] In some embodiments, in compounds I-3’ and I-4’,

[0111] n’ is 0, 1, 2, 3, 4, 5, 6, or 7;

[0112] each R 1 is each independently D, -OH, halogen, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogen;

[0113] o is 0 or 2;

[0114] each R 2-2 is each independently halogen, preferably F;

[0115] L’ is -O-, -(CH2) m - or -(CD2) m -, preferably -O- or -(CH2) m -;

[0116] m is 1 or 2;

[0117] R 3 is C1-C6 alkyl, C3-C8 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 ;

[0118] R 3-1 is C1-C3 alkyl;

[0119] R 3-2 is D or halogen;

[0120] R 4 is methyl or methyl substituted with 1-3 D.

[0121] In some embodiments, in compounds I-3’ and I-4’,

[0122] is

[0123] n is 0, 1, 2, or 3,

[0124] each R 1 is each independently D, halogen, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogen;

[0125] k is 0, 1, 2, or 3 (more preferably, k is 0);

[0126] t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6);

[0127] each R 1-1 and R 1-2 is each independently D, -OH, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH);

[0128] o is 0 or 2;

[0129] each R 2-2 is each independently halogen, preferably F;

[0130] L' is -0-, -(CH2) m - or -(CD2) m -, preferably -0- or -(CH2) m -;

[0131] m is 1 or 2;

[0132] R 3 is Ci-C6alkyl, C3-C8cycloalkyl substituted with one or more R 3-1 , -Si(Ci-C6alkyl)3, or Ci-C6alkyl substituted with one or more R 3-2 ;

[0133] R 3-1 is Ci-C3alkyl;

[0134] R 3-2 is D or halogen;

[0135] R 4 is methyl or methyl substituted with 1-3 D.

[0136] In some embodiments, the compound I is compound I-1, I-2, I-3, or I-4:

[0137] wherein n, R 1 , R 2 , q, R 2-2 , o, L, and R 3 are as previously described.

[0138] In some embodiments, in compounds I-1 and I-2,

[0139] n is 0 or 1;

[0140] each R1 Each is independently a halogen, an -O-C1-C6 alkyl group, or a C1-C6 alkyl group substituted with one or more halogens;

[0141] q is 0, 1, or 2;

[0142] Each R 2 Each can be independently D, -OH, or a halogen;

[0143] L represents -O- or -(CH2). m -, m is 1 or 2;

[0144] R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3;

[0145] R 3-1 It is a C1-C3 alkyl group.

[0146] In some embodiments, compounds I-3 and I-4,

[0147] n is 0 or 1;

[0148] Each R 1 Each is independently a halogen, an -O-C1-C6 alkyl group, or a C1-C6 alkyl group substituted with one or more halogens;

[0149] o is 0 or 2;

[0150] Each R 2-2 Each is an independent halogen, preferably F;

[0151] L represents -O- or -(CH2). m -, m is 1 or 2;

[0152] R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3;

[0153] R 3-1 It is a C1-C3 alkyl group.

[0154] In some embodiments, in compound I-1,

[0155] n is 1;

[0156] R 1 It is a halogen; preferably F;

[0157] q is 0, 1, or 2;

[0158] Each R 2each independently -OH or halogen;

[0159] L is O or -CH2-;

[0160] R 3 is C1-C6 alkyl, C3-C8 cycloalkyl substituted by one or more R 3-1 ; or -Si(C1-C6 alkyl)3;

[0161] R 3-1 is C1-C3 alkyl.

[0162] In some embodiments, in compound I-2,

[0163] n is 1 ;

[0164] R 1 is halogen; preferably F;

[0165] q is 0;

[0166] L is -CH2-;

[0167] R 3 is C1-C6 alkyl or C3-C8 cycloalkyl substituted by one or more R 3-1 ; preferably t-butyl.

[0168] R 3-1 is C1-C3 alkyl.

[0169] In some embodiments, in compounds I-3 and I-4,

[0170] n is 1 ;

[0171] R 1 is halogen; preferably F;

[0172] o is 0 or 2;

[0173] each R 2-2 is independently halogen, preferably F;

[0174] L is -CH2-;

[0175] R 3 is C1-C6 alkyl; preferably t-butyl.

[0176] In some embodiments, in compound I-1,

[0177] n is 1 ;

[0178] R 1 is halogen; preferably F;

[0179] q is 0 or 1 ;

[0180] R2 halogen; preferably F;

[0181] L is -CH2-;

[0182] R 3 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R 3-1 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R 3-1 C1-C3 alkyl; preferably R 3 tert-butyl,

[0183] In some embodiments, the compounds I-3 and I-4 are:

[0184] n is 1;

[0185] R 1 halogen; preferably F;

[0186] o is 0;

[0187] L is -CH2-;

[0188] R 3 C1-C6 alkyl; preferably tert-butyl.

[0189] In some embodiments, the compound I’ is compound I-1-1’, I-1-2’ (e.g., I-1-2-1’ or I-1-2-2’), I-3-1’ (e.g., I-3-1-1’ or I-3-1-2’), or I-4-1’ (e.g., I-4-1-1’ or I-4-1-2’):

[0190] (e.g. ) (e.g. ) or (e.g. ),

[0191] wherein o is 0, 1, or 2, n’, R 1 , R 2 , R 2-2 , L’, R 3 , and R 4 are as previously described.

[0192] In some embodiments, the compounds I-1-1’ are:

[0193] n’ is 0, 1, 2, 3, 4, 5, 6, or 7;

[0194] each R 1each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen;

[0195] L' is -0-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0196] R 3 is Ci-C6alkyl, C3-C8cycloalkyl substituted with one or more R 3-1 , -Si(Ci-C6alkyl)3, or Ci-C6alkyl substituted with one or more R 3-2 ;

[0197] R 3-1 is Ci-C3alkyl;

[0198] R 3-2 is D or halogen;

[0199] R 4 is methyl or methyl substituted with 1-3 D.

[0200] In some embodiments, in compounds I-1-1',

[0201] is

[0202] n is 0, 1, 2, or 3,

[0203] each R 1 is independently D, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen;

[0204] k is 0, 1, 2, or 3 (more preferably, k is 0);

[0205] t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6);

[0206] each R 1-1 and R 1-2 is independently D, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH);

[0207] L' is -0-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0208] R3 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R 3-1 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R 3-2 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R

[0209] R 3-1 C1-C3 alkyl;

[0210] R 3-2 D or halogen;

[0211] R 4 methyl or methyl substituted with 1-3 D.

[0212] In some embodiments, in I-1-2’ (e.g., I-1-2-1’ or I-1-2-2’),

[0213] n’ is 0, 1, 2, 3, 4, 5, 6, or 7;

[0214] each R 1 is each independently D, -OH, halogen, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogen;

[0215] R 2 D, -OH, or halogen;

[0216] L’ is -O-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0217] R 3 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R 3-1 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R 3-2 C1-C6 alkyl, C3-C8 cycloalkyl substituted with one or more R

[0218] R 3-1 C1-C3 alkyl;

[0219] R 3-2 D or halogen;

[0220] R 4 methyl or methyl substituted with 1-3 D.

[0221] In some embodiments, in I-1-2’ (e.g., I-1-2-1’ or I-1-2-2’),

[0222] is

[0223] n is 0, 1, 2, or 3,

[0224] each R 1 is independently D, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen;

[0225] k is 0, 1, 2, or 3 (more preferably, k is 0);

[0226] t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6);

[0227] each R 1-1 and R 1-2 is independently D, -OH, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH);

[0228] R 2 is D, -OH, or halogen;

[0229] L' is -0-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0230] R 3 is Ci-C6alkyl, C3-C8cycloalkyl substituted with one or more R 3-1 , -Si(Ci-C6alkyl)3, or Ci-C6alkyl substituted with one or more R 3-2 ;

[0231] R 3-1 is Ci-C3alkyl;

[0232] R 3-2 is D or halogen;

[0233] R 4 is methyl or methyl substituted with 1-3 D.

[0234] In some embodiments, in compounds I-3-1' (e.g., I-3-1-1' or I-3-1-2') and I-4-1' (e.g., I-4-1-1' or I-4-1-2'),

[0235] n' is 0, 1, 2, 3, 4, 5, 6, or 7;

[0236] each R 1 ' is independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen;

[0237] o is 0 or 2;

[0238] each R 2-2 is independently halogen, preferably F;

[0239] L' is -0-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0240] R 3 is C1-C6 alkyl, C3-C8 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 ;

[0241] R 3-1 is C1-C3 alkyl;

[0242] R 3-2 is D or halogen;

[0243] R 4 is methyl or methyl substituted by 1-3 D.

[0244] In some embodiments, in compounds I-3-1' (e.g., I-3-1-1' or I-3-1-2') and I-4-1' (e.g., I-4-1-1' or I-4-1-2'), each R

[0245] is

[0246] n is 0, 1, 2 or 3,

[0247] each R 1 is independently D, halogen, -O-C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogen;

[0248] k is 0, 1, 2 or 3 (more preferably, k is 0);

[0249] t is 0, 1, 2, 3, 4, 5 or 6 (more preferably, t is 0, 1, 2, 4 or 6);

[0250] each R 1-1 and R 1-2 are each independently D, -OH, halogen (e.g., fluorine), -O-C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogen (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH);

[0251] o is 0 or 2;

[0252] each R 2-2 is independently halogen, preferably F;

[0253] L' is -0-, -(CH2) m - or -(CD2) m -, m is 1 or 2;

[0254] R 3 is C1-C6 alkyl, C3-C8 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 ;

[0255] R 3-1 is C1-C3 alkyl;

[0256] R 3-2 is D or halogen;

[0257] R 4 is methyl or methyl substituted by 1-3 D.

[0258] In some embodiments, the compound I-1 is compound I-1-1, I-1-2 (e.g. I-1-2-1 or I-1-2-2), I-3-1 (e.g. I-3-1-1 or I-3-1-2) or I-4-1 (e.g. I-4-1-1 or I-4-1-2): (e.g. ) (e.g. ) (e.g. );

[0259] wherein n, R 1 , R 2 , R 2-2 , o, L and R 3 are as defined above.

[0260] In some embodiments, in compound I-1-1,

[0261] n is 0 or 1;

[0262] each R 1 is independently halogen, -O-C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogen;

[0263] L is -0- or -(CH2) m -, m is 1 or 2;

[0264] R3 C1-C6 alkyl, C3-C8 cycloalkyl substituted by one or more R 3-1 C3-C8 cycloalkyl substituted by one or more R

[0265] R 3-1 C1-C3 alkyl.

[0266] In some embodiments, in compound I-1-2 (e.g., I-1-2-1 or I-1-2-2),

[0267] n is 0 or 1 ;

[0268] each R 1 each independently halogen, -O-C1-C6 alkyl, or C1-C6 alkyl substituted by one or more halogen;

[0269] R 2 D, -OH, or halogen;

[0270] L is -O- or -(CH2) m -, m is 1 or 2;

[0271] R 3 C1-C6 alkyl, C3-C8 cycloalkyl substituted by one or more R 3-1 C3-C8 cycloalkyl substituted by one or more R

[0272] R 3-1 C1-C3 alkyl.

[0273] In some embodiments, in compound I-3-1 (e.g., I-3-1-1 or I-3-1-2) or I-4-1 (e.g., I-4-1-1 or I-4-1-2),

[0274] n is 0 or 1 ;

[0275] each R 1 each independently halogen, -O-C1-C6 alkyl, or C1-C6 alkyl substituted by one or more halogen;

[0276] o is 0 or 2;

[0277] each R 2-2 each independently halogen, preferably F;

[0278] L is -O- or -(CH2) m -, m is 1 or 2;

[0279] R 3 C1-C6 alkyl, C3-C8 cycloalkyl substituted by one or more R 3-1 C3-C8 cycloalkyl substituted by one or more R

[0280] R 3-1 is C1-C3 alkyl.

[0281] In some embodiments, in compound I-1-1,

[0282] n is 1 ;

[0283] R 1 is halogen; preferably F;

[0284] L is O or -CH2-;

[0285] R 3 is C1-C6 alkyl, C3-C8 cycloalkyl substituted by one or more R 3-1 or -Si(C1-C6 alkyl)3;

[0286] R 3-1 is C1-C3 alkyl.

[0287] In some embodiments, in compound I-1-2 (e.g. I-1-2-1 or I-1-2-2),

[0288] n is 1 ;

[0289] R 1 is halogen; preferably F;

[0290] R 2 is halogen; preferably F;

[0291] L is O or -CH2-;

[0292] R 3 is C1-C6 alkyl or C3-C8 cycloalkyl substituted by one or more R 3-1 ;

[0293] R 3-1 is C1-C3 alkyl.

[0294] In some embodiments, in compound I-3-1 (e.g. I-3-1-1 or I-3-1-2) or I-4-1 (e.g. I-4-1-1 or I-4-1-2),

[0295] n is 1 ;

[0296] R 1 is halogen; preferably F;

[0297] o is 0 or 2;

[0298] each R 2-2 is independently halogen, preferably F;

[0299] L is -CH2-;

[0300] R 3 is C1-C6 alkyl; preferably tert-butyl.

[0301] In some embodiments, in compound I-1-1,

[0302] n is 1 ;

[0303] R 1 is halogen; preferably F;

[0304] L is -CH2-;

[0305] R 3 is C1-C6 alkyl, C3-C8 cycloalkyl substituted by one or more R 3-1 or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; preferably R 3 is tert-butyl,

[0306] In some embodiments, in compound I-1-2 (e.g. I-1-2-1 or I-1-2-2),

[0307] n is 1 ;

[0308] R 1 is halogen; preferably F;

[0309] R 2 is halogen; preferably F;

[0310] L is -CH2-;

[0311] R 3 is C1-C6 alkyl or C3-C8 cycloalkyl substituted by one or more R 3-1 or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; preferably R 3 is tert-butyl,

[0312] In some embodiments, in compound I-3-1 (e.g. I-3-1-1 or I-3-1-2) or I-4-1 (e.g. I-4-1-1 or I-4-1-2),

[0313] n is 1 ;

[0314] R 1 is halogen; preferably F;

[0315] o is 0;

[0316] L is -CH2-;

[0317] R3 Ci-C6alkyl; preferably tert-butyl.

[0318] In some embodiments,

[0319] In some embodiments,

[0320] In some embodiments, (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), or (e.g. ).

[0321] In some embodiments, preferably

[0322] In some embodiments,

[0323] In some embodiments, the compound of the application is any one of the following compounds: (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. (e.g. ) (e.g. )​​​​​ (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. )

[0324] In some embodiments, the above compounds can be prepared by the methods of the Preparations.

[0325] In some embodiments, the compound is the single isomer that elutes first (relatively short retention time) under the following conditions: a chiral column Chiralcel AD-3; eluent A is CO2; eluent B is ethanol containing 0.2% ammonia; gradient elution; flow rate 4 mL / min; preferably the conditions are: a chiral column Chiralcel AD-3, 50 mm x 4.6 mm, 3 μm particle size; eluent A is CO2; eluent B is ethanol containing 0.2% ammonia; elution gradient A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate 4 mL / min; column temperature 35 °C (preferably the instrument is a Waters UPC® C with PDA detector and SQ detector); preferably, the single isomer that elutes first (relatively short retention time) under the conditions has a retention time of about 1.27 min.

[0326] In some embodiments, the compound is the single isomer which elutes later (retention time relatively long) under the following conditions: chromatographic column: Chiralcel AD-3; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; gradient elution; flow rate: 4 mL / min; preferably the conditions are: chromatographic column: Chiralcel AD-3, 50 mm x 4.6 mm, particle size 3 μm; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; elution gradient: A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate: 4 mL / min; column temperature: 35°C (preferably the instrument is a Waters UPC® C with PDA detector and SQ detector); preferably, under the conditions, the single isomer which elutes later (retention time relatively long) has a retention time of about 1.69 min.

[0327] In some embodiments, the compound is the single isomer which elutes first (retention time relatively short) under the following conditions: chromatographic column: Chiralcel AD-3; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; gradient elution; flow rate: 4 mL / min; preferably the conditions are: chromatographic column: Chiralcel AD-3, 50 mm x 4.6 mm, particle size 3 μm; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; elution gradient: A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate: 4 mL / min; column temperature: 35°C (preferably the instrument is a Waters UPC® C with PDA detector and SQ detector); preferably, under the conditions, the single isomer which elutes first (retention time relatively short) has a retention time of about 1.1 min.

[0328] In some embodiments, the compound is the single isomer which elutes later (retention time relatively long) under the following conditions: chromatographic column: Chiralcel AD-3; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; gradient elution; flow rate: 4 mL / min; preferably the conditions are: chromatographic column: Chiralcel AD-3, 50 mm x 4.6 mm, 3 μm particle size; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; elution gradient: A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate: 4 mL / min; column temperature: 35°C (preferably the instrument is a Waters UPC® C with PDA detector and SQ detector); preferably, under the conditions, the single isomer which elutes later (retention time relatively long) has a retention time of about 1.32 min.

[0329] In some embodiments, the compound is the single isomer which elutes first (retention time relatively short) under the following conditions: chromatographic column: Chiralcel AD-3; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; gradient elution; flow rate: 4 mL / min; preferably the conditions are: chromatographic column: Chiralcel AD-3, 50 mm x 4.6 mm, 3 μm particle size; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; elution gradient: A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate: 4 mL / min; column temperature: 35°C (preferably the instrument is a Waters UPC® C with PDA detector and SQ detector); preferably, under the conditions, the single isomer which elutes first (retention time relatively short) has a retention time of about 1.16 min.

[0330] In some embodiments, the compound is the single isomer which elutes later (retention time relatively long) under the following conditions: chromatographic column: Chiralcel AD-3; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; gradient elution; flow rate: 4 mL / min; preferably the conditions are: chromatographic column: Chiralcel AD-3, 50 mm x 4.6 mm, 3 μm particle size; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; elution gradient: A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate: 4 mL / min; column temperature: 35°C (preferably the instrument is a Waters UPC® C with PDA detector and SQ detector); preferably, under the conditions, the single isomer which elutes later (retention time relatively long) has a retention time of about 1.58 min.

[0331] In some embodiments, the compound is the single isomer which elutes first (retention time relatively short) under the following conditions: chromatographic column: Chiralcel OD-3; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; gradient elution; flow rate: 4 mL / min; preferably the conditions are: chromatographic column: Chiralcel OD-3, 50 mm x 4.6 mm, 3 μm particle size; eluent A: CO2; eluent B: ethanol with 0.2% ammonia; elution gradient: A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate: 4 mL / min; column temperature: 35°C (preferably the instrument is a Waters UPC® C with PDA detector and SQ detector); preferably, under the conditions, the single isomer which elutes first (retention time relatively short) has a retention time of about 1.01 min.

[0332] In some embodiments, the compound is the single isomer of the compound of formula III' elutes with a longer retention time under the following conditions: a chiral column Chiralcel OD-3; eluent A is CO2; eluent B is ethanol containing 0.2% ammonia; gradient elution; flow rate 4 mL / min; preferably the conditions are: a chiral column Chiralcel OD-3, 50 mm x 4.6 mm, 3 μm particle size; eluent A is CO2; eluent B is ethanol containing 0.2% ammonia; elution gradient A / B = 95 / 5 to 60 / 40 in 1.5 min; hold 60 / 40 for 1 min; A / B = 95 / 5 for 0.5 min; flow rate 4 mL / min; column temperature 35 °C (preferably the instrument is a Waters UPC C with PDA and SQ detectors); preferably, under the conditions, the single isomer of the compound of formula III' elutes with a longer retention time of about 1.17 min.

[0333] The present application provides a compound III',

[0334] wherein ring A, L', R 3 and R 4 are as previously described.

[0335] In some embodiments, the compound III' is a compound III.

[0336] The present application provides a compound III,

[0337] wherein ring A, L, R 3 and R 4 are as previously described.

[0338] In some embodiments, the compound III' is any one of the following:

[0339] (e.g. ),

[0340] (e.g. ) or

[0341] (e.g. ).

[0342] The present application provides a process for preparing a compound as described above, or a pharmaceutically acceptable salt thereof, according to Scheme 1' or Scheme 2':

[0343] Scheme 1': comprising the step of subjecting compound II' or a salt thereof and compound III' to a coupling reaction as shown below in the presence of a solvent, preferably in the presence of a catalyst, preferably a Pd catalyst, and a base, to yield compound I';

[0344] Scheme 2': comprising the step of subjecting compound IV' and compound V' to a reaction as shown below in the presence of a solvent, preferably in the presence of a strong base, to yield compound I';

[0345] wherein n', R 1 , ring A, L', R 3 , and R 4 are as defined above.

[0346] The present application provides a method of preparing a compound as described above, or a pharmaceutically acceptable salt thereof, which is Scheme 1 or Scheme 2:

[0347] Scheme 1 comprises the step of subjecting compound II or a salt thereof and compound III to a coupling reaction as shown below in the presence of a solvent, preferably in the presence of a catalyst, preferably a Pd catalyst, and a base, to yield compound I;

[0348] Scheme 2 comprises the step of subjecting compound IV and compound V to a reaction as shown below in the presence of a solvent, preferably in the presence of a strong base, to yield compound I;

[0349] wherein n, R 1 , ring A, L, R 3 , and R 4 are as defined above.

[0350] In some embodiments, when R 3 is -Si(Ci-C6alkyl)3, the method of preparing compound I' is Scheme 2'.

[0351] In some embodiments, when R 3 is -Si(Ci-C6alkyl)3, the method of preparing compound I is Scheme 2.

[0352] In some embodiments, in Scheme 1', the salt of compound II' is a hydrochloride salt.

[0353] In some embodiments, in Scheme 1, the salt of compound II is a hydrochloride salt.

[0354] In some embodiments, in the schemes 1, 1', 2 and 2', the solvent can be a conventional solvent for such reactions in the art, each independently preferably an organic solvent, more preferably an alicyclic ether solvent, for example dioxane and / or tetrahydrofuran, preferably dioxane.

[0355] In some embodiments, in the schemes 1 and 1', 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(l1) tetra(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium.

[0356] In some embodiments, in the schemes 1 and 1', 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.

[0357] The present application provides a compound prepared by the above-mentioned preparation method or a pharmaceutically acceptable salt thereof.

[0358] The present application provides a pharmaceutical composition comprising:

[0359] (1) a compound as mentioned above or a pharmaceutically acceptable salt thereof or a compound prepared by the above-mentioned preparation method or a pharmaceutically acceptable salt thereof, and

[0360] (2) a pharmaceutically acceptable excipient.

[0361] The present application provides use of a compound as mentioned above or a pharmaceutically acceptable salt thereof, a compound prepared by the above-mentioned preparation method or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as mentioned above as a KCNQ2 / 3 channel opener.

[0362] 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 as an experimental use, for example: as a standard sample or a control sample to provide a comparison, or prepared into a kit according to the conventional method in the art to provide a rapid detection of the opening effect of the KCNQ2 / 3 channel.

[0363] The present application provides a compound as mentioned above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as mentioned above for use as a medicament.

[0364] The present application provides use of a compound as mentioned above or a pharmaceutically acceptable salt thereof, a compound prepared by the above-mentioned preparation method or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as mentioned above in the preparation of a medicament for preventing or treating a disease.

[0365] In some embodiments, the disease is epilepsy, depression, anxiety or pain.

[0366] In some embodiments, the epilepsy includes, but is not limited to, focal seizures or generalized tonic-clonic seizures.

[0367] The present application provides use of a compound as described above or a pharmaceutically acceptable salt thereof, or a compound prepared by a process 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.

[0368] In some embodiments, the disease associated with KCNQ2 / 3 channel can be epilepsy, depression, anxiety or pain.

[0369] In some embodiments, the epilepsy includes, but is not limited to, focal seizures or generalized tonic-clonic seizures.

[0370] 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 prevention or treatment a prophylactically or therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof, or a compound prepared by a process as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0371] In some embodiments, the disease associated with KCNQ2 / 3 channel can be epilepsy, depression, anxiety or pain.

[0372] In some embodiments, the epilepsy includes, but is not limited to, focal seizures or generalized tonic-clonic seizures.

[0373] Terminology

[0374] In the present application, "about" means a fluctuation range of ±0.4, preferably a fluctuation range of ±0.2 (e.g. ±0.1).

[0375] 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 relatively acidic functionalities, base addition salts can be obtained by contacting the compound with a sufficient amount of the desired pharmaceutically acceptable base in a suitable inert solvent. Where the compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the compound with a sufficient amount of the desired pharmaceutically acceptable acid in a suitable inert solvent. See, e.g., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0376] In the present application, the term "a structural fragment is connected to the rest of the molecule via the site" refers to the structural fragment is connected to the rest of the molecule via the site. For example, In the present application, the term "a structural fragment is connected to the rest of the molecule via the site" refers to the structural fragment is connected to the rest of the molecule via the site. For example,

[0377] In the present application, the term "a structural fragment is connected to the rest of the molecule via the site" refers to the structural fragment is connected to the rest of the molecule via the site. For example,

[0378] In the present application, the term "one or more" refers to 1 or more than 1, for example, 1, 2, 3, 4, 5, 6, 7, etc., preferably 1, 2 or 3.

[0379] In the present application, the term "a group B substituted with one or more groups A" refers to the groups A can be located at the same position or different positions of the group B when the groups A are "multiple".

[0380] In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0381] ​In the present invention, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon radical having a specified number of carbon atoms. C1-C6 alkyl refers to 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, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-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.

[0382] In the present invention, the term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon radical 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 cycloalkyl, or a bridged cycloalkyl, and the like, preferably a spirocyclic cycloalkyl, which shares one carbon atom between the monocyclic rings. Cycloalkyl includes, but is not limited to:

[0383] In the present invention, when the substituted polycyclic structure is wherein indicates that the substitution site can be at any position on both rings, for example, the substitution site is at any position on ring A and / or the substitution site is at any position on ring B for example indicates that R 1 is substituted at any position on the phenyl ring and / or at any position on the piperidine ring.

[0384] In the present invention, when the substituted polycyclic structure is wherein indicates that the substitution site can be at any position on both rings, for example, the substitution site is at any position on ring A indicates that R 1 is substituted at any position on the phenyl ring and / or at any position on the piperidine ring.

[0385] In the present invention, the term "saturated carbocycle" refers to a saturated carbocycle having a specified number of carbocyclic atoms (e.g., 3- to 8-membered, 5- to 7-membered). It is a monocyclic. "Saturated carbocycle" includes, but is not limited to:

[0386] ​​In the present application, the term "pharmaceutically acceptable excipients" refers to all substances contained in the pharmaceutical preparation in addition to the active pharmaceutical ingredient, which are generally divided into two categories of excipients and additional agents. For details, please refer to 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).

[0387] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be arbitrarily combined, i.e. to obtain each preferred example of the present application.

[0388] The reagents and raw materials used in the present application are commercially available.

[0389] The positive progress effect of the present application is that the compound containing aromatic fused ring of the present application has one or more of the following effect advantages: (1) novel structure; (2) good opening effect on KCNQ2 / 3 channel; (3) relatively weak KCNQ4 and KCNQ5 opening activity; (4) good KCNQ2 / 3 selectivity; (5) small toxic side effects; (6) good in vivo efficacy, with good anti-seizure effect; (7) excellent safety window; (8) good brain-blood ratio; (9) good brain and blood concentration. The more optimal compound and the most optimal compound of the present application have two or more of the above-mentioned effect advantages. BRIEF DESCRIPTION OF DRAWINGS

[0390] Figure 1 is a molecular stereoscopic structure ellipsoidal diagram of compound I-18a.

[0391] Figure 2 is a molecular stereoscopic structure ellipsoidal diagram of compound I-21a. DETAILED DESCRIPTION

[0392] The present application will be further described below, but the present application is not limited in the scope described. The experimental methods not specified in the following examples are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0393] Preparation Example 1: Synthesis of compound I-1

[0394] Step 1: Synthesis of intermediate 1-2

[0395] Compound 1-1 (1.18 g, 4.50 mmol) and compound 1-1a (527.72 mg, 4.50 mmol) were dissolved with 20 mL of dioxane, and cesium carbonate (3.67 g, 11.26 mmol), Pd2(dba)3(412.51 mg, 450.48 µmol) and Xantphos (390.99 mg, 675.72 µmol) were added in turn. The reaction system was stirred at 105 ℃ for 3 h. LCMS monitored the complete consumption of raw materials, and the product was generated. The reaction liquid was filtered, the filtrate was concentrated to a residue under reduced pressure, and the residue was prepared by silica gel column chromatography (Silica Flash Column, mobile phase gradient: ethyl acetate / petroleum ether 0-100%; flow rate: 40 mL / min) to obtain intermediate 1-2 as a colorless oil (850 mg, yield: 62.92%). 20 g Silica Flash Column, flow phase gradient: ethyl acetate / petroleum ether 0-100%; flow rate: 40 mL / min) to obtain intermediate 1-2 as a colorless oil (850 mg, yield: 62.92%). 13 H 17 BrNO2 + [M+H] + Calculated = 298.04, 300.04 Found = 298.0, 300.0.

[0396] Step 2: synthesis of intermediate 1-3

[0397] Intermediate 1-2 (510 mg, 1.71 mmol) was dissolved with 5 mL of trifluoroacetic acid, and the reaction system was stirred at 20 ℃ for 10 min. LCMS monitored the complete consumption of raw materials, and the product was generated. The reaction liquid was concentrated to a residue under reduced pressure, dissolved with 10 mL of ethyl acetate, and washed with saturated sodium bicarbonate solution (5 mL x 2). After the organic phase was separated, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain intermediate 1-3 as a light yellow solid (254 mg, crude). LCMS (ESI): m / z C8H9BrN + [M+H] + Calculated = 197.99, 199.99 Found = 198.0, 200.0.

[0398] Step 3: synthesis of intermediate 1-4

[0399] Intermediate 1-3 (70 mg, 353.43 µmol) was dissolved with 5 mL of dichloromethane, and triethylamine (357.63 mg, 3.53 mmol) was added. To the above solution, compound 1-3a (95.15 mg, 706.86 µmol) was added dropwise at 25 ℃. After the dropwise addition was completed, the system was continuously stirred at 25 ℃ for 1 h. TLC (petroleum ether / ethyl acetate = 3:1) monitored the complete reaction of raw materials, and the main product was generated. The reaction was concentrated to a residue under reduced pressure, and the residue was prepared by silica gel column chromatography ( 4g Intermediate 1-4 was prepared as a colorless oil (75 mg, yield: 71.64%) by silica flash column chromatography (Column size: 40x150mm; mobile phase: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) from intermediate 1-3 (100 mg, 337.61 pmol). LCMS (ESI): m / z C 14 H 19 BrNO + [M+H] + Calc. = 296.06, 298.06 Found = 296.0, 298.0.

[0400] Step 4: Synthesis of compound I-1

[0401] Intermediate 1-4 (100 mg, 337.61 pmol) was dissolved in 5 mL of dioxane and compound 1-4a (63.35 mg, 337.61 pmol), cesium carbonate (109.99 mg, 337.61 pmol), RuPhos Pd G3 (28.24 mg, 33.76 pmol) were added. The reaction was stirred at 105 °C for 3 h. LCMS was used to monitor the consumption of starting material and the formation of product. The reaction was filtered, the filtrate was concentrated to a residue under reduced pressure and preparative reversed-phase column chromatography (Column size: C18 150x40mm; mobile phase: [Phase A: water (0.075% formic acid) - Phase B: acetonitrile]; gradient: 65%-95% B in 7 min) was used to obtain compound I-1 as a white solid (16.4 mg, yield: 13.66%), LCMS (ESI): m / z C 23 H 28 FN2O + [M+H] + Calc. = 367.22 Found = 367.2. 1 H NMR (400 MHz, DMSO-d6) d ppm 9.37 (s, 1H), 7.28-7.21 (m, 1H), 7.14-7.05 (m, 1H), 7.04-6.93 (m, 2H), 6.70-6.57 (m, 1H), 4.32 (s, 2H), 3.55-3.46 (m, 2H), 3.24-3.12 (m, 2H), 3.07-2.96 (m, 2H), 2.91-2.80 (m, 2H), 2.16 (s, 2H), 1.05-0.96 (m, 9H).

[0402] Preparation 2: Synthesis of compound I-2

[0403] Step 1: Synthesis of intermediate 2-1

[0404] Intermediate 1-3 (300 mg, 1.51 mmol) was dissolved in 4 mL of ethanol and N-iodosuccinimide (340.78 mg, 1.51 mmol) was added. The reaction was stirred at 25 °C for 1 h. TLC (petroleum ether / ethyl acetate = 7:1) monitoring showed that the starting material was consumed completely and the main product was generated. The reaction was quenched with 4 mL of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (4 mL x 2). The saturated brine was washed, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to get an oily residue which was purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give intermediate 2-1 as a white solid (480 mg, yield: 97.82%). 12g Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give intermediate 2-1 as a white solid (480 mg, yield: 97.82%). LCMS (ESI): m / z C8H8BrIN + .[M+H] + Calculated = 323.89, 325.89 Found = 323.8, 325.8.

[0405] Step 2: Synthesis of intermediate 2-2

[0406] Intermediate 2-1 (400 mg, 1.23 mmol) was dissolved in 10 mL of dichloromethane and triethylamine (249.89 mg, 2.47 mmol, 343.72 μί) was added. To the above reaction, compound 1-3a (332.40 mg, 2.47 mmol, 343.03 μί) was added dropwise at 25 °C. After the addition was completed, the reaction was stirred at 25 °C for 1 h. LCMS monitoring showed that the starting material was consumed completely and the main product was generated. The reaction was concentrated under reduced pressure to get a residue which was purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give intermediate 2-2 as a white solid (505 mg, yield: 97.26%). 20g Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give intermediate 2-1 as a white solid (480 mg, yield: 97.82%). LCMS (ESI): m / z C8H8BrIN 14 H 18 BrINO + .[M+H] + Calculated = 421.96, 423.96 Found = 421.9, 423.9.

[0407] Step 3: Synthesis of intermediate 2-3

[0408] Intermediate 2-2 (500.00 mg, 1.18 mmol) was dissolved in 8 mL of dioxane, and methyl boronic acid 2-2a (283.63 mg, 4.74 mmol), sodium carbonate solution (1 M, 3.55 mL) and tetrakis(triphenylphosphine)palladium (136.88 mg, 118.46 μmol) were added in turn. The reaction system was stirred at 100 °C for 1 h. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was dissolved in 10 mL of ethyl acetate, and the organic phase was washed with saturated ammonium chloride solution (5 mL x 2) and saturated brine (5 mL x 2). After separation, the organic phase 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 (Silica Flash Column, mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 2-3 as a white solid (245 mg, yield: 66.92%). 20 g Silica Flash Column, mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 2-3 as a white solid (245 mg, yield: 66.92%). 15 H 21 BrNO + [M+H] + Calcd = 310.08, 312.08 Found = 310.0, 312.0.

[0409] Step 4: Synthesis of compound I-2

[0410] Intermediate 2-3 (50 mg, 161.17 μmol) was dissolved in 4 mL of dioxane, and compound 1-4a (30.24 mg, 161.17 μmol), cesium carbonate (52.51 mg, 161.17 μmol) and RuPhos Pd G3 (13.48 mg, 16.12 μmol) were added in turn. The reaction system was stirred at 105 °C for 3 h. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain compound I-2 as a white solid (21 mg, yield: 34.24%). 20 g Silica Flash Column, mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain compound I-2 as a white solid (21 mg, yield: 34.24%). 24 H 30 FN2O + [M+H] + Calcd = 381.23 Found = 381.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1 H), 7.24 (dd, J=6.3, 7.8 Hz, 1 H), 7.06 - 6.93 (m, 2 H), 6.53 (s, 1 H), 4.34 (s, 2 H), 3.50 (t, J=5.9 Hz, 2 H), 3.17 - 3.13 (m, 2 H), 2.91 - 2.82 (m, 4 H), 2.13 (s, 2 H), 2.11 (s, 3 H), 1.02 (s, 9 H).

[0411] Preparation Example 3: Synthesis of compound I-3

[0412] Step 1: Synthesis of intermediates 3-2a and 3-2b

[0413] Compound 3-1 (2.35 g, 17.65 mmol) was dissolved in 10 mL of dichloromethane and N-bromosuccinimide (3.14 g, 17.65 mmol) was added. The reaction system was stirred at 20 °C for 2 hours. TLC (petroleum ether: ethyl acetate = 3: 1) monitoring showed that the raw material was consumed completely and two products were generated. The reaction solution was quenched with 10 mL of saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5 mL x 3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain an oily residue, which was subjected to silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 3-2a as a gray solid (700 mg, yield: 18.7%). 60 g Silica Flash Column, flow phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 3-2a as a gray solid (700 mg, yield: 18.7%). LCMS (ESI): m / z C9H 11 BrN + [M+H] + Calculated = 212.01, 214.01 Found = 211.9, 214.0. 1 H NMR (400 MHz, CD3Cl) δ ppm 7.20 - 7.07 (m, 1 H), 6.48 - 6.39 (m, 1 H), 3.00 - 2.93 (m, 2 H), 2.88 - 2.80 (m, 2 H), 2.17 - 2.12 (m, 2 H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 144.47, 143.96, 129.77, 129.54, 114.25, 104.64, 34.83, 31.13, 23.61. Intermediate 3-2b was obtained as a gray solid (150 mg, yield: 4.0%). LCMS (ESI): m / z C9H11 BrN + .[M+H] + Calculated = 212.01, 214.01 Found = 212.0, 213.9. 1 H NMR (400 MHz, CD3Cl) δ ppm 7.27-7.19 (m, 1 H), 6.67-6.48 (m, 1 H), 2.97-2.85 (m, 2 H), 2.82-2.72 (m, 2 H), 2.23-2.09 (m, 2 H).

[0414] Step 2: Synthesis of compound I-3

[0415] Referring to the synthesis method of step 3 and step 4 in preparation example 1, the corresponding raw material is replaced, and intermediate 3-2a is used as the raw material to prepare compound I-3, which is a white solid. LCMS (ESI): m / z C 24 H 30 FN2O + .[M+H] + Calculated = 381.23 Found = 381.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (s, 1 H), 7.27-7.13 (m, 2 H), 7.05-6.91 (m, 2 H), 6.77 (d, J = 8.5 Hz, 1 H), 4.09 (s, 2 H), 3.19 (t, J = 5.7 Hz, 2 H), 2.91 (t, J = 5.4 Hz, 2 H), 2.84 (t, J = 7.2 Hz, 2 H), 2.77 (t, J = 7.3 Hz, 2 H), 2.17 (s, 2 H), 1.98-196 (m, 2 H), 1.03 (s, 9 H).

[0416] Preparation Example 4: Synthesis of compound I-4

[0417] Step 1: Synthesis of intermediate 4-1

[0418] Intermediate 3-2a (500 mg, 2.36 mmol) was dissolved in 8 mL of methanol, and NIS (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 purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1) to give compound 3-2b as a white solid. 20g Intermediate 4-1 was prepared as a grey black solid (780 mg, yield: 97.89%) from Intermediate 4 (1 g, 2.97 mmol) using a Silica Flash Column with a mobile phase gradient of 0-30% ethyl acetate / pet. ether; flow rate: 30 mL / min. LCMS (ESI): m / z C9H 10 BrIN + .[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 CNMR (101 MHz, DMSO) δ ppm 144.80, 144.28, 137.74, 129.83, 105.71, 81.18, 34.82, 32.48, 23.72.

[0419] Step 2: Synthesis of Intermediate 4-2

[0420] Intermediate 4-1 (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 1-3a (477.91 mg, 3.55 mmol, 493.20 μί) was added drop wise with stirring. After completion of the addition, the reaction mixture was stirred at 25 °C for 1 h. TLC (pet. ether / ethyl acetate = 6:1) monitoring showed complete consumption of starting material and formation of product. The reaction mixture 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 / pet. ether; flow rate: 30 mL / min) to obtain Intermediate 4-2 as a white solid (710 mg, yield: 91.89%). 12g Intermediate 4-2 was prepared as a white solid (710 mg, yield: 91.89%) from Intermediate 4 (1 g, 2.97 mmol) using a Silica Flash Column with a mobile phase gradient of 0-40% ethyl acetate / pet. ether; flow rate: 30 mL / min. LCMS (ESI): m / z C 15 H 20 BrIN + .[M+H] + Calculated = 435.98, 437.98 Found = 436.0, 438.0. 1 H NMR (400 MHz, DMSO) δ ppm 9.46 (s, 1 H), 7.82 (s, 1 H), 2.91 -2.81 (m, 4 H), 2.20 (s, 2 H), 2.06-1.95 (m, 2 H), 1.06 (s, 9 H); 13C NMR (101 MHz, DMSO-d6) d 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.

[0421] Step 3: Synthesis of intermediate 4-3

[0422] Intermediate 4-2 (500 mg, 1.15 mmol) was dissolved in 10 mL of dioxane, and methyl boronic acid 2-2a (274.51 mg, 4.59 mmol), sodium carbonate solution (1 M, 3.44 mL) and tetrakis(triphenylphosphine)palladium (132.48 mg, 114.65 μmol) were added in turn. The reaction system was stirred at 100 °C for 1 h. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was dissolved in 15 mL of ethyl acetate, and the organic phase was washed with saturated ammonium chloride solution (8 mL x 2) and saturated brine (5 mL x 2). After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-50%, 30 mL / min) to obtain intermediate 4-3 as an off-white solid (120 mg, yield: 32.28%). 20g Silica Flash Column, flow phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 4-3 as an off-white solid (120 mg, yield: 32.28%). LCMS (ESI): m / z C 16 H 23 BrNO + [M+H] + Calcd = 324.10, 326.09 Found = 324.1, 326.1. 1 H NMR (400 MHz, DMSO-d6) d ppm 9.23 (s, 1H), 7.23 (s, 1H), 2.89-2.79 (m, 4H), 2.18 (s, 2H), 2.13 (s, 3H), 2.02-1.95 (m, 2H), 1.05 (s, 9H); 13 C NMR (101 MHz, DMSO-d6) d ppm 169.51, 143.51, 142.20, 135.22, 132.94, 130.82, 116.34, 49.13, 34.60, 32.96, 31.01, 30.23, 23.94, 17.97.

[0423] Step 4: Synthesis of compound I-4

[0424] Compound I-4 was prepared according to the procedure described in Step 4 of Preparation 2, by replacing the corresponding starting materials with intermediate 4-3 as the starting material. Compound I-4 was prepared as a white solid. LCMS (ESI): m / z C 25 H 32 FN2O + .[M+H] + Calcd = 395.25 Found = 395.2. 1 H NMR (400 MHz, DMSO-d6) d ppm 9.04 (s, 1 H), 7.21 (t, J = 7.0 Hz, 1 H), 7.05 - 6.94 (m, 2 H), 6.68 (s, 1 H), 4.11 (s, 2 H), 3.21 (t, J = 5.6 Hz, 2 H), 2.93 (t, J = 5.3 Hz, 2 H), 2.83 (t, J = 7.0 Hz, 2 H), 2.70 (t, J = 7.3 Hz, 2 H), 2.17 (s, 2 H), 2.13 (s, 3 H), 2.02 - 1.88 (m, 2 H), 1.06 (s, 9 H).

[0425] Preparation 5: Synthesis of compound I-5

[0426] Step 1: Synthesis of intermediate 5-1

[0427] Intermediate 4-1 (187.52 mg, 554.85 m mol) and compound 5-1a (75.9 mg, 665.82 m mol) were dissolved in 3 mL of ethyl acetate, and 50% n- butylphosphinic anhydride ethyl acetate solution (799.56 mg, 1.11 mmol) and pyridine (438.89 mg, 5.55 mmol, 447.84 m L) were added dropwise. The reaction system was stirred at 50 °C for 1 hour. LCMS monitored the complete consumption of raw materials and the generation of product. The reaction system was concentrated to a residue, and intermediate 5-1 was prepared by silica gel column chromatography (4 g 4g Silica Flash Column, mobile phase gradient: 0 - 50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) as a white solid (176 mg, yield: 73.06%). LCMS (ESI): m / z C 15 H 18 BrINO + .[M+H] + Calcd = 433.96, 435.96 Found = 433.9, 436.0.

[0428] Step 2: Synthesis of intermediate 5-2

[0429] Intermediate 5-2 was prepared according to the procedure described in Step 3 of Preparation 4, replacing the corresponding starting material, using intermediate 5-1 as the starting material. LCMS (ESI): m / z C 16 H 21 BrNO + [M+H] + Calc. = 322.08, 324.08 Found = 322.1, 324.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (s, 1 H), 7.24 (s, 1 H), 2.92-2.72 (m, 4 H), 2.19 (s, 2 H), 2.13 (s, 3 H), 2.04-1.94 (m, 2 H), 1.13 (s, 3 H), 0.55-0.50 (m, 2 H), 0.33-0.29 (m, 2 H).

[0430] Step 3: Synthesis of compound I-5

[0431] Compound I-5 was prepared according to the procedure described in Step 4 of Preparation 2, replacing the corresponding starting material, using intermediate 5-2 as the starting material. LCMS (ESI): m / z C 25 H 30 FN2O + [M+H] + Calc. = 393.23 Found = 393.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.98 (s, 1 H), 7.21 (t, J=7.1 Hz, 1 H), 7.05-6.92 (m, 2 H), 6.69 (s, 1 H), 4.11 (s, 2 H), 3.21 (t, J=5.8 Hz, 2 H), 2.93 (t, J=5.6 Hz, 2 H), 2.83 (t, J=7.0 Hz, 2 H), 2.70 (t, J=7.3 Hz, 2 H), 2.18 (s, 2 H), 2.13 (s, 3 H), 2.01-1.90 (m, 2 H), 1.15 (s, 3 H), 0.57-0.50 (m, 2 H), 0.36-0.29 (m, 2 H).

[0432] Preparation 6: Synthesis of compound I-6

[0433] Step 1: Synthesis of intermediate 6-2

[0434] Compound 6-1 (3.00 g, 20.37 mmol) was dissolved in 15 mL of DMF, and the system was cooled to 0 °C. N-bromosuccinimide (3.80 g, 21.39 mmol) was dissolved in 25 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 temperature was slowly increased to 10 °C, and the reaction was stirred for 2 h. LCMS monitoring showed that the raw material was completely consumed, and the product was generated. The reaction liquid was added dropwise to saturated sodium bicarbonate aqueous solution (150 mL) for quenching, and the system was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (30 mL x 2) and saturated brine (20 mL x 2) in sequence. After the organic phase was separated, 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 (Silica Flash Column, mobile phase gradient: 0-45% ethyl acetate / petroleum ether; flow rate: 25 mL / min) to prepare intermediate 6-2 as a brown-black solid (4.18 g, yield: 90.72%). 60 g Silica Flash Column, mobile phase gradient: 0-45% ethyl acetate / petroleum ether; flow rate: 25 mL / min) to prepare intermediate 6-2 as a brown-black solid (4.18 g, yield: 90.72%). 10 H 13 BrN + [M+H] + Calcd = 226.02, 228.02 Found = 226.0, 228.0.

[0435] Step 2: Synthesis of intermediate 6-3

[0436] Intermediate 6-2 (4.12 g, 18.22 mmol) was dissolved in 42 mL of anhydrous ethanol, the system was cooled to 0 °C, and N-iodosuccinimide (4.51 g, 20.04 mmol) was added. The reaction system was stirred at 0 °C for 1 h, and then slowly increased to 25 °C, and stirring was continued for 2 h. LCMS monitoring showed that the raw material was basically consumed. The reaction liquid was concentrated to dryness to obtain a residue, which was subjected to silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 25 mL / min) to prepare intermediate 6-3 as a brown-red solid (4.68 g, yield: 72.97%). 60 g Silica Flash Column, mobile phase gradient: 0-45% ethyl acetate / petroleum ether; flow rate: 25 mL / min) to prepare intermediate 6-2 as a brown-black solid (4.18 g, yield: 90.72%). 10 H 12 BrIN + [M+H] + Calcd = 351.92, 353.92 Found = 351.9, 353.9. 1H NMR (400 MHz, DMSO) δ ppm 7.59 (s, 1 H), 4.87 (s, 2 H), 2.57-2.49 (m, 2 H), 2.58-2.37 (m, 2 H), 1.75-1.60 (m, 4 H); 13 C NMR (101 MHz, DMSO) δ ppm 145.62, 137.40, 136.33, 124.19, 112.06, 81.19, 30.65, 26.34, 22.50, 22.47.

[0437] Step 3: Synthesis of intermediate 6-4

[0438] Intermediate 5-la (1.30 g, 11.36 mmol) was dissolved in 15 mL of anhydrous toluene and dichlorosulfoxide (1.49 g, 12.50 mmol) was added dropwise. After the addition was complete, the system was heated to 75 °C and stirred for 3 hours. The reaction solution was cooled to 0 °C and diisopropylethylamine (3.67 g, 28.41 mmol) was added dropwise. Intermediate 6-3 (2.00 g, 5.68 mmol) was dissolved in 15 mL of anhydrous toluene and added dropwise to the above reaction system. After the addition was complete, the temperature was raised to 25 °C and stirring was continued for 2 hours. LCMS monitoring showed that the raw material was substantially consumed completely. The reaction solution was diluted with 50 mL of ethyl acetate and 50 mL of water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-35% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 6-4 as an off-white solid (2.02 g, yield: 79.35%). 60 g Silica Flash Column, flow phase gradient: 0-35% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 6-4 as an off-white solid (2.02 g, yield: 79.35%). 16 H 20 BrINO + [M+H] + Calculated = 447.98, 449.98; Found = 447.9, 449.9. 1 H NMR (400 MHz, DMSO) δ ppm 9.30 (s, 1 H), 7.94 (s, 1 H), 2.64-2.60 (m, 4 H), 2.22-2.19 (m, 2 H), 1.69-1.65 (m, 4 H), 1.17 (s, 3 H), 0.56-0.53 (m, 2 H), 0.32-0.29 (m, 2 H); 13C NMR (101 MHz, DMSO) d ppm 170.07, 139.57, 138.99, 138.11, 137.37, 124.56, 99.08, 45.23, 30.61, 27.06, 24.05, 22.43, 22.22, 14.19, 12.94.

[0439] Step 4: Synthesis of intermediate 6-5

[0440] Referring to the synthetic method of step 3 in Preparation 4, replacing the corresponding raw material, intermediate 6-5 was prepared from intermediate 6-4 as a white solid. LCMS (ESI): m / z C 17 H 23 BrNO + [M + H] + Calcd = 336.10, 338.09 Found = 336.1, 338.1. 1 H NMR (400 MHz, DMSO-d6) d ppm 9.00 (s, 1 H), 7.35 (s, 1 H), 2.70 - 2.52 (m, 4 H), 2.20 (s, 2 H), 2.09 (s, 3 H), 1.75 - 1.58 (m, 4 H), 1.14 (s, 3 H), 0.56 - 0.47 (m, 2 H), 0.35 - 0.26 (m, 2 H); 13 C NMR (101 MHz, DMSO-d6) d ppm 170.04, 137.60, 135.30, 135.18, 134.06, 130.80, 123.25, 45.27, 30.49, 26.05, 23.86, 22.81, 22.38, 18.08, 14.43, 13.06.

[0441] Step 5: Synthesis of compound I-6

[0442] Referring to the synthetic method of step 4 in Preparation 2, replacing the corresponding raw material, compound I-6 was prepared from intermediate 6-5 as a white solid. LCMS (ESI): m / z C 26 H 32 FN2O + [M + H] + Calcd = 407.25 Found = 407.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.09 (dd, J = 5.8, 8.0 Hz, 1 H), 6.93 - 6.79 (m, 3 H), 4.01 (s, 2 H), 3.14 (t, J = 5.5 Hz, 2 H), 2.98 (d, J = 4.8 Hz, 2 H), 2.75 (t, J = 5.9 Hz, 2 H), 2.66 (s, 2 H), 2.31 (s, 2 H), 2.19 (s, 3 H), 1.86 - 1.75 (m, 2 H), 1.74 - 1.64 (m, 2 H), 1.23 (s, 3 H), 0.64 - 0.57 (m, 2 H), 0.45 - 0.36 (m, 2 H).

[0443] Preparation Example 7: Synthesis of compound I-7

[0444] Step 1: Synthesis of intermediate 7-1

[0445] Intermediate 4-1 (2.00 g, 5.9 mmol) was dissolved in 20 mL of dioxane, and methyl boronic acid 2-2a (0.72 g, 12.0 mmol), tetrakis(triphenylphosphine)palladium (1.00 g, 0.86 mmol), cesium carbonate (5.80 g, 17.8 mmol) were added in turn. The reaction system was protected by nitrogen, and stirred at 100 °C for 2 hours. LCMS monitoring showed that the raw material was completely consumed, and the product was generated. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was dissolved in 40 mL of ethyl acetate, and the organic phase was washed with saturated ammonium chloride solution (15 mL x 2), saturated brine (15 mL x 1). After separation, the organic phase 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 (40 g, Silica Flash Column, mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 7-1 as a white solid (550 mg, yield: 41.22%). 40 g Silica Flash Column, flow phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 7-1 as a white solid (550 mg, yield: 41.22%). 10 H 13 BrN + [M+H] + Calculated = 226.02, 228.02 Found = 226.0, 228.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.90 (s, 1 H), 4.70 (s, 2 H), 2.75 (t, J = 7.5 Hz, 4 H), 2.03 (s, 3 H), 2.02 - 1.94 (m, 2 H); 13C NMR (101 MHz, DMSO-d6) δ ppm 142.23, 141.49, 130.46, 129.33, 121.79, 104.38, 34.59, 31.34, 23.99, 17.36.

[0446] Step 2: Synthesis of intermediate 7-2

[0447] Intermediate 7-1 (0.50 g, 2.29 mmol) was dissolved in 10 mL of tert-butyl alcohol and di-tert-butyl dicarbonate (1.00 g, 4.4 mmol) was added. The reaction was stirred at 60 °C for 7 h. TLC (petroleum ether / ethyl acetate = 10:1) was used to monitor the consumption of starting material. The reaction was diluted with 20 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (ISCO CombiFlash® Rf rapid liquid chromatography; column size: 12 g Silica Flash Column, mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 35 mL / min) to afford intermediate 7-2 as a white solid (650 mg, yield: 87%). H 15 H 21 BrNO2 + [M+H] + Calcd = 326.08, 328.07 Found [M-Boc+H] + = 226.1, 228.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 7.21 (s, 1H), 2.91-2.78 (m, 4H), 2.13 (s, 3H), 2.05-1.94 (m, 2H), 1.43 (s, 9H); 13 C NMR (101 MHz, DMSO) δ 153.60, 143.70, 142.26, 135.53, 132.78, 130.84, 116.10, 78.96, 34.62, 32.45, 28.60, 24.03, 17.69.

[0448] Step 3: Synthesis of intermediate 7-3

[0449] Intermediate 7-2 (550 mg, 1.69 mmol) and compound 1-4a (379.62 mg, 2.02 mmol) were dissolved in 15 mL of dioxane, and RuPhos Pd G3 (141.01 mg, 168.59 µmol), cesium carbonate (1.37 g, 4.21 mmol) were added in turn. The reaction system was stirred at 105 °C for 3 h. LCMS monitored the complete consumption of raw materials and the generation of products. The reaction liquid was filtered, the filtrate was concentrated under reduced pressure to a residue, and the residue was prepared by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 7-3 as a white solid (560 mg, yield: 83.77%), LCMS (ESI): m / z C 20g Silica Flash Column, flow phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 7-3 as a white solid (560 mg, yield: 83.77%), LCMS (ESI): m / z C 24 H 30 FN2O2 + [M+H] + Calcd = 397.23 Found = 397.2.

[0450] Step 4: synthesis of intermediate 7-4

[0451] Intermediate 7-3 (500 mg, 1.26 mmol) was dissolved in 6 mL of dichloromethane, and trifluoroacetic acid (4.31 g, 37.83 mmol) was added dropwise. The reaction liquid was stirred at 25 °C for 1 h. LCMS monitored the safe consumption of raw materials and the generation of products. The reaction liquid was concentrated under reduced pressure to a residue, and was dissolved in 30 mL of ethyl acetate, washed with saturated brine (5 mL x 2), water (5 mL), saturated sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7-4 as a white solid (370 mg, crude).

[0452] Step 5: synthesis of compound I-7

[0453] Intermediate 7-4 (209.46 mg, 706.71 µmol) and compound 7-4a (2.07 g, 14.13 mmol) were dissolved in 4 mL of tetrahydrofuran. To the above solution, LiHMDS tetrahydrofuran solution (2 M, 7.07 mL) was added dropwise. After the dropwise addition was completed, the reaction liquid was stirred at 20 °C for 1 h. TLC (petroleum ether: ethyl acetate = 10:1) monitored the complete consumption of raw materials and the generation of products. The reaction liquid was concentrated under reduced pressure to a residue, and the residue was prepared by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain compound I-7 as a white solid (100 mg, yield: 48.48%, purity: 95.0%). 20g Compound I-7 was prepared by using a Silica Flash Column, mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 30 mL / min) as a white solid (38 mg, yield: 13.02%). LCMS (ESI): m / z C 24 H 32 FN2OSi + .[M+H] + Calculated = 411.23 Found = 411.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (s, 1 H), 7.20 (t, J = 7.2 Hz, 1 H), 7.03 - 6.95 (m, 2 H), 6.66 (s, 1 H), 4.09 (s, 2 H), 3.19 (t, J = 5.7 Hz, 2 H), 2.95 - 2.89 (m, 2 H), 2.81 (t, J = 7.0 Hz, 2 H), 2.69 (t, J = 7.5 Hz, 2 H), 2.12 (s, 3 H), 1.98 - 1.92 (m, 2 H), 1.89 (s, 2 H), 0.13 (s, 9 H).

[0454] Preparation Example 8: Synthesis of compound I-8

[0455] Step 1: Synthesis of intermediate 8-1

[0456] Referring to the synthesis method of step 2 in Preparation Example 4, replacing the corresponding raw material, compound 8-1 was prepared as a white solid by using intermediate 6-3 as the raw material. LCMS (ESI): m / z C 16 H 22 BrINO + .[M+H] + Calculated = 449.99, 451.99 Found = 449.9, 451.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (s, 1 H), 7.93 (s, 1 H), 2.71 - 2.57 (m, 4 H), 2.22 (s, 2 H), 1.75 - 1.60 (m, 4 H), 1.07 (s, 9 H); 13 C NMR (101 MHz, DMSO) δ 170.10, 139.53, 139.13, 138.15, 137.32, 124.50, 99.01, 48.98, 31.19, 30.42, 29.89, 27.18, 22.41, 22.22.

[0457] Step 2: Synthesis of intermediate 8-2

[0458] Compound 8-2 was prepared according to the procedure described in Step 3 of Preparation 4, replacing the corresponding starting material with intermediate 8-1, as a white solid. LCMS (ESI): m / z C 17 H 25 BrNO + .[M+H] + Calcd = 338.11, 340.11 Found = 338.1, 340.1. 1 HNMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1H), 7.34 (s, 1H), 2.76-2.52 (m, 4H), 2.21-2.18 (m, 2H), 2.09 (s, 3H), 1.73-1.60 (m, 4H), 1.05 (s, 9H); 13 C NMR (101 MHz, DMSO) δ 169.98, 137.54, 135.39, 135.10, 134.03, 130.80, 123.20, 49.01, 31.03, 30.50, 30.28, 26.15, 22.79, 22.37, 18.24.

[0459] Step 3: Synthesis of compound I-8

[0460] Compound I-8 was prepared according to the procedure described in Step 4 of Preparation 4, replacing the corresponding starting material with intermediate 8-2, as a white solid. LCMS (ESI): m / z C 26 H 34 FN2O + .[M+H] + Calcd = 409.26, Found = 409.3. 1 H NMR (400 MHz, CDCl3) δ ppm 7.11-6.97 (m, 1H), 6.93-6.82 (m, 3H), 6.49 (s, 1H), 4.06 (s, 2H), 3.25-3.11 (m, 2H), 2.99 (s, 2H), 2.75 (s, 2H), 2.66 (t, J = 6.3 Hz, 2H), 2.30 (s, 2H), 2.22 (s, 3H), 1.83-1.75 (m, 2H), 1.73-1.66 (m, 2H), 1.16 (s, 9H).

[0461] Preparation 9: Synthesis of compound I-9

[0462] Step 1: Synthesis of intermediate 9-1

[0463] Compound 3-2a (1.5 g, 7.07 mmol) was dissolved in 10 mL of DMF, and the system was cooled to 0 °C. A solution of N-chlorosuccinimide (991.25 mg, 7.42 mmol) in DMF (5 mL) was added slowly dropwise. After the addition was completed, the temperature was slowly raised to 10 °C, and the reaction was stirred for 3 hours. LCMS monitoring showed that the raw material was completely consumed, and the product was generated. The reaction solution was added dropwise to saturated aqueous sodium bicarbonate solution (50 mL) for quenching, and the system was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (10 mL x 2) and saturated brine (10 mL x 2) in sequence. After the organic phase was separated, 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 (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 3-2b as a colorless oil (1.2 g, yield: 68.84%). 40g Silica Flash Column, flow phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 35 mL / min) to obtain intermediate 9-1 as a colorless oil (1.2 g, yield: 68.84%). LCMS (ESI): m / z C9H 10 BrClN + [M+H] + Calcd = 245.97, 247.97 Found = 246.0, 248.0. 1 H NMR (400 MHz, CDCl3) δ ppm 7.24 (s, 1H), 2.95-2.89 (m, 2H), 2.87-2.81 (m, 2H), 2.20-2.12 (m, 2H).

[0464] Step 2: Synthesis of intermediate 9-2

[0465] Referring to the synthesis method of step 3 in preparation example 1, the corresponding raw material was replaced, and intermediate 9-1 was used as the raw material to prepare compound 9-2 as a white solid. LCMS (ESI): m / z C 15 H 20 BrClNO + [M+H] + Calcd = 344.04, 346.04 Found = 344.0, 346.0. 1 H NMR (400 MHz, CDCl3) δ ppm 7.39 (s, 1H), 6.99 (s, 1H), 2.98-2.94 (m, 4H), 2.24 (s, 2H), 2.15-2.10 (m, 2H), 1.07 (s, 9H).

[0466] Step 3: Synthesis of compound 1-9

[0467] Compound 1-9 was prepared according to the procedure for the synthesis of Step 4 in Preparation 1, substituting the corresponding starting materials, using intermediate 9-2 as the starting material. Compound 1-9 was prepared as a white solid. LCMS (ESI): m / z C 24 H 29 ClFN2O + .[M+H] + Calcd = 415.19 Found = 415.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1 H), 7.31 - 7.14 (m, 1 H), 7.07 - 6.94 (m, 2 H), 6.87 (s, 1 H), 4.16 (s, 2 H), 3.34 - 3.25 (m, 2 H), 3.19 - 3.17 (m, 2 H), 2.94 - 2.92 (m, 2 H), 2.87 (t, J = 7.2 Hz, 2 H), 2.72 (t, J = 7.2 Hz, 2 H), 2.18 (s, 2 H), 1.06 (s, 9 H).

[0468] Preparation 10: Synthesis of compound 1-10

[0469] Step 1: Synthesis of intermediate 10-3

[0470] Compound 10-3 was prepared according to the procedure for the synthesis of intermediate 6-3 in Preparation 6, substituting the corresponding starting materials, using compound 10-1 as the starting material. Compound 10-3 was prepared as a light brown solid. LCMS (ESI): m / z C8H8BrINO + .[M+H] + Calcd = 339.88, 341.88 Found = 340.0, 341.9. 1 H NMR (400 MHz, CDCl3) δ ppm 7.64 (s, 1 H), 5.11 - 5.09 (m, 2 H), 5.06 - 5.03 (m, 2 H).

[0471] Step 2: Synthesis of intermediate 10-4

[0472] Compound 10-4 was prepared according to the procedure for the synthesis of intermediate 7-1 in Preparation 7, substituting the corresponding starting materials, using compound 10-3 as the starting material. Compound 10-4 was prepared as a yellow solid. LCMS (ESI): m / z C9H 11 BrNO + .[M+H] + Calcd = 228.00, 230.00 Found = 228.1, 230.0.

[0473] Step 3: Synthesis of intermediate 10-5

[0474] Compound 10-5 was prepared according to the procedure described in Step 1 of Preparation 8, replacing the corresponding starting material, using compound 10-4 as the starting material. Compound 10-5 was obtained as a white solid. 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, CDC13) δ ppm 6.67 (s, 1 H), 5.08 (d, J=16.2 Hz, 4 H), 2.26 (s, 2 H), 2.25 (s, 3 H), 1.13 (s, 9 H).

[0475] Step 4: Synthesis of compound 1-10

[0476] Compound 1-10 was prepared according to the procedure described in Step 4 of Preparation 1, replacing the corresponding starting material, using compound 10-5 as the starting material. Compound 1-10 was obtained as a white solid. LCMS (ESI): m / z C 24 H 30 FN2O2 + [M+H] + Calcd = 397.23 Found = 397.3. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (s, 1 H), 7.23-7.20 (m, 1 H), 7.02-6.98 (m, 2 H), 6.76 (s, 1 H), 5.03 (s, 2 H), 4.80 (s, 2 H), 4.15 (s, 2 H), 3.22 (t, J=5.7 Hz, 2 H), 2.89 (t, J=5.5 Hz, 2 H), 2.17 (s, 3 H), 2.15 (s, 2 H), 1.03 (s, 9 H).

[0477] Preparation 11: Synthesis of compound 1-11

[0478] Compound 1-11 was prepared according to the procedure described in Preparation 10, replacing the corresponding starting material, using compound 11-1 as the starting material. Compound 1-11 was obtained as a white solid. LCMS (ESI): m / z C 24 H 30 FN2O2 + [M+H] + Calcd = 397.23 Found = 397.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, 1 H), 7.19 (dd, J=6.0, 9.1 Hz, 1 H), 7.04 - 6.87 (m, 2 H), 6.60 (s, 1 H), 4.51 (t, J=8.8 Hz, 2 H), 4.17 (s, 2 H), 3.41 - 3.37 (m, 2 H), 3.00 (t, J=8.8 Hz, 2 H), 2.87 (t, J=5.5 Hz, 2 H), 2.16 (s, 2 H), 2.08 (s, 3 H), 1.04 (s, 9 H).

[0479] Preparation Example 12: Synthesis of compound I-12

[0480] Step 1: Synthesis of intermediate 12-2

[0481] Compound 12-1 (3 g, 16.92 mmol) and BAST (9.09 g, 41.10 mmol, 9 mL) were placed in a 100 mL round-bottom flask. The reaction system was stirred rapidly at 80 °C for 1 h. TLC (petroleum ether: ethyl acetate = 8: 1) monitoring showed that the starting material was consumed completely and the product spot was generated. The reaction system was cooled to 0 °C. Under rapid stirring, 100 mL of water was slowly added to the above system. The mixture was extracted with ethyl acetate (20 mL x 2), and 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 (Silica Flash Column, mobile phase gradient: 0-47% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to give intermediate 12-2 as a colorless oil (900 mg, yield: 26.69%). 40 g Silica Flash Column, flow phase gradient: 0-47% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to give intermediate 12-2 as a colorless oil (900 mg, yield: 26.69%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.26 (d, J=8.1 Hz, 1 H), 7.80 (d, J=7.2 Hz, 1 H), 7.57 - 7.46 (m, 1 H), 3.54 - 3.38 (m, 2 H), 2.73 - 2.46 (m, 2 H).

[0482] Step 2: Synthesis of intermediate 12-3

[0483] Intermediate 12-2 (0.9 g, 4.52 mmol) was dissolved in 20 mL of ethanol, and iron powder (1.26 g, 22.60 mmol) and ammonium chloride solution (4 M, 5.65 mL) were added sequentially. The reaction system was stirred at 80 °C for 1 h. LCMS monitoring showed that the starting material was consumed completely, and the reaction liquid was filtered through diatomite, and the filtrate was concentrated under reduced pressure to a residue, which was purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-47% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to give intermediate 12-3 as a colorless oil (1.2 g, yield: 95.00%). 12 g Intermediate 12-3 was prepared as a light brown solid (710 mg, yield: 92.85%) from Intermediate 12-2 (750 mg, 4.14 mmol) using a Silica Flash Column with a mobile phase gradient of 0-60% ethyl acetate / petroleum ether; flow rate: 35 mL / min. LCMS (ESI): m / z C9H9BrF2N [M+H]+at 270.0 (100%), 272.0 (30%). 10 F2N + [M+H] + Calculated = 170.08, Found = 170.1.

[0484] Step 3: Synthesis of Intermediate 12-4

[0485] Intermediate 12-3 (700 mg, 4.14 mmol) was dissolved in 10 mL of acetonitrile and N-bromosuccinimide (736.47 mg, 4.14 mmol) was added. The reaction was stirred at 0 °C for 10 min. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the consumption of starting material and the formation of new product. 10 mL of saturated aqueous sodium bicarbonate solution was added dropwise to the reaction and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was combined and washed with water (10 mL x 2), saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 5:1) to give Intermediate 12-4 as a light brown solid (890 mg, yield: 86.66%). 12g Intermediate 12-4 was prepared as a light brown solid (890 mg, yield: 86.66%) from Intermediate 12-3 (700 mg, 4.14 mmol) using a Silica Flash Column with a mobile phase gradient of 0-45% ethyl acetate / petroleum ether; flow rate: 30 mL / min. LCMS (ESI): m / z C9H9BrF2N [M+H]+at 270.0 (100%), 272.0 (30%). + [M+H] + Calculated = 247.99, 249.99, Found = 248.1, 250.1. 1 H NMR (400 MHz, CDC13) δ ppm 7.20 (d, J = 8.3 Hz, 1 H), 6.54 (d, J = 8.3 Hz, 1 H), 2.80-2.66 (m, 2 H), 2.64-2.48 (m, 2 H).

[0486] Step 4: Synthesis of Intermediate 12-5

[0487] Intermediate 12-4 (890 mg, 3.59 mmol) was dissolved in 10 mL of acetic acid and N-iodosuccinimide (807.18 mg, 3.59 mmol) was added. The reaction system was stirred at 80 °C for 10 min. TLC (petroleum ether: ethyl acetate = 7:1) monitoring showed that the raw material was consumed completely and a new product was generated. The reaction solution was diluted with 30 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium bicarbonate (10 mL x 2), water (10 mL x 2), saturated brine (10 mL x 2) in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to a residue under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1) to give intermediate 12-5 as a white solid (1.2 g, yield: 89.38%). 20g Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give intermediate 12-5 as a white solid (1.2 g, yield: 89.38%). LCMS (ESI): m / z C9H8BrF2IN + [M+H] + Calcd = 373.89, 375.88 Found = 373.9, 375.9.

[0488] Step 5: Synthesis of compound I-12

[0489] Referring to the synthesis method of step 2 to step 4 in preparation example 10, the corresponding raw materials were replaced, and compound I-12 was prepared as a white solid with compound 12-5 as the raw material. LCMS (ESI): m / z C 25 H 30 F3N2O + [M+H] + Calcd = 431.23 Found = 431.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (s, 1H), 7.22-7.15 (m, 1H), 7.01 (d, J = 9.2 Hz, 2H), 6.89 (s, 1H), 4.22 (s, 2H), 3.42 (t, J = 5.7 Hz, 2H), 2.92 (t, J = 5.3 Hz, 2H), 2.80-2.72 (m, 2H), 2.47-2.43 (m, 2H), 2.19 (s, 3H), 2.18 (s, 2H), 1.05 (s, 9H).

[0490] Preparation Example 13: Synthesis of compound I-13

[0491] Reference to the synthetic method of Preparation Example 4, replace the corresponding raw material, with compound 13-1 (preparation method reference US2020 / 0071344A1) as raw material, compound I-13 was prepared as a white solid. LCMS (ESI): m / z C 25 H 30 FN2O2 + .[M+H] + Calcd = 409.23 Found = 409.3. 1 H NMR (400 MHz, DMSO-d6) d ppm 9.20 (s, 1H), 7.21 (dd, J = 5.9, 8.4 Hz, 1H), 7.10 - 6.94 (m, 2H), 6.83 (s, 1H), 4.29 (s, 2H), 3.39 - 3.35 (m, 2H), 3.07 (t, J = 5.4 Hz, 2H), 2.90 - 2.78 (m, 2H), 2.63 - 2.54 (m, 2H), 2.23 (s, 3H), 2.22 (s, 2H), 1.09 - 1.05 (m, 9H).

[0492] Preparation Example 14: Synthesis of compound I-14

[0493] Compound I-13 (70 mg, 171.36 µmol) was dissolved in 5 mL of ethanol, and sodium borohydride (19.45 mg, 514.07 µmol) was added. The reaction system was stirred at 50 ℃ for 2 hours. LCMS monitored the complete consumption of raw materials, the reaction liquid was diluted with 10 mL of saturated ammonium chloride solution, and extracted with ethyl acetate (5 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, and purified by silica gel column chromatography (12 g 12g Silica Flash Column, flow phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 35 mL / min) to prepare intermediate I-14 as a white solid (52 mg, yield: 73.92%). LCMS (ESI): m / z C 25 H 32 FN2O2 + .[M+H] + Calcd = 411.24 Found = 411.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (s, 1 H), 7.22 - 7.12 (m, 1 H), 7.06 - 6.93 (m, 2 H), 6.71 (s, 1 H), 5.10 (d, J=3.0 Hz, 1 H), 4.93 (d, J=2.3 Hz, 1 H), 4.32 (d, J=15.1 Hz, 1 H), 4.11 (d, J=15.4 Hz, 1 H), 3.74 - 3.61 (m, 1 H), 3.27 - 3.21 (m, 2 H), 3.02 - 2.82 (m, 3 H), 2.22 - 2.04 (m, 6 H), 1.93 - 1.78 (m, 1 H), 1.05 (s, 9 H).

[0494] Preparation Example 15: Synthesis of compound I-15

[0495] Step 1: Synthesis of intermediate 15-1

[0496] Compound 4-2 (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. The raw material was monitored by LCMS to be 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 15-1 as a light yellow solid (9.2 g, yield: 54.07%). 220 g Silica Flash Column, flow phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 15-1 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, 1 H), 8.33 (s, 1 H), 2.97 - 2.84 (m, 2 H), 2.69 - 2.58 (s, 2 H), 2.24 (s, 2 H), 1.08 (s, 9 H); 13C NMR (101 MHz, DMSO-d6) d 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.

[0497] Step 2: Synthesis of intermediate 15-2

[0498] Following the synthetic procedure of Step 3 in Preparation 4, replacing appropriate starting materials with compound 15-1, compound 15-2 was prepared as a white solid. LCMS (ESI): m / z C 16 H 21 BrNO2 + [M + H] + Calcd = 338.08, 340.07 Found = 338.1, 340.1. 1 H NMR (400 MHz, DMSO-d6) d 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) d 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.

[0499] Step 3: Synthesis of intermediate I-15

[0500] Following the synthetic procedure of Step 4 in Preparation 1, replacing appropriate starting materials with compound 15-2, compound I-15 was prepared as a white solid. LCMS (ESI): m / z C 25 H 30 FN2O2 + [M + H] + Calcd = 409.23 Found = 409.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.20 (s, 1 H), 7.22 (dd, J=5.8, 8.2 Hz, 1 H), 7.18 (s, 1 H), 7.08 - 6.98 (m, 2 H), 4.20 (s, 2 H), 3.31 - 3.29 (m, 2 H), 2.97 (d, J=5.4 Hz, 4 H), 2.58 (dd, J=4.6, 6.9 Hz, 2 H), 2.21 (s, 2 H), 2.16 (s, 3 H), 1.05 (s, 9 H).

[0501] Preparation Example 16: synthesis of compound I-16

[0502] Step 1: synthesis of intermediate 16-1

[0503] Intermediate 15-2 (3.0 g, 8.9 mmol) was dissolved in 15 mL of methanol, and fluorinating agent (Selectfluor) (3.5 g, 9.8 mmol) and concentrated sulfuric acid (180 μL) were added in turn. The reaction system was added to 100°C, and stirred to reflux for 3 hours. Then it was reduced to room temperature, and 0.3 M aqueous sulfuric acid (36 mL) was added. The reaction system was continued to reflux for 1 hour. LCMS monitoring showed that the raw material was consumed and the product was generated. The reaction solution was concentrated to a residue, and dissolved in 300 mL of dichloromethane. The organic phase was washed with water (100 mL x 3) in turn, saturated brine (100 mL x 2), 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 to obtain intermediate 16-1 as a white solid (2.8 g, yield: 88.31 %). LCMS (ESI): m / z C 16 H 20 BrFNO2 + [M+H] + Calculated = 356.07, 358.06 Found = 356.0, 358.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (s, 1 H), 7.90 (s, 1 H), 5.43 (ddd, J=50.9, 7.8, 4.1 Hz, 1 H), 3.55 - 3.41 (m, 1 H), 3.05 - 2.91 (m, 1 H), 2.25 (s, 2 H), 2.21 (s, 3 H), 1.06 (s, 9 H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 197.75, 169.96, 147.63, 140.58, 137.21, 131.11, 130.59, 117.81, 91.97, 49.11, 33.55, 33.33, 31.18, 30.20, 17.68.

[0504] Step 2: Synthesis of intermediate 16-2

[0505] Intermediate 16-1 (500 mg, 1.40 mmol) was dissolved in 50 mL of methanol, the reaction system was cooled to 0 °C, and sodium borohydride (160 mg, 4.20 mmol) was added. The reaction system was stirred at 0 °C for 2 hours. LCMS monitoring showed that the raw material was completely consumed. The reaction solution was quenched with saturated ammonium chloride solution, and 100 mL of dichloromethane solution was added. After the organic phase was separated, it 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, which was prepared by silica gel column chromatography to give intermediate 16-2 as a white solid (460 mg, yield: 91.71 %). LCMS (ESI): m / z C 16 H 22 BrFNO2 + .[M+H] + Calcd = 358.08, 360.08 Found = 358.1, 360.1. 1 H NMR (400 MHz, CDCl3) δ ppm 7.60 (s, 1H), 7.36 (s, 1H), 5.24-5.19 (m, 1H), 3.35-3.21 (m, 1H), 3.15-3.00 (m, 2H), 2.31 (s, 2H), 2.25 (s, 3H), 1.15 (s, 9H).

[0506] Step 3: Synthesis of compound I-16

[0507] Referring to the synthesis method of step 4 in preparation example 1, replace the corresponding raw material, and use intermediate 16-2 as the raw material to prepare compound I-16 as a white solid. LCMS (ESI): m / z C 25 H 31 F2N2O2 + .[M+H] + Calcd = 429.23 Found = 429.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 7.25 - 7.18 (m, 1 H), 7.05 - 6.97 (m, 2 H), 6.82 (s, 1 H), 5.14 - 4.94 (m, 1 H), 4.98 (q, J=5.6 Hz, 1 H), 4.90 - 4.86 (m, 1 H), 4.20 - 4.03 (m, 2 H), 3.28 - 3.23 (m, 1 H), 3.20 - 3.12 (m, 1 H), 3.10 - 2.99 (m, 2 H), 2.99 - 2.88 (m, 2 H), 2.21 (d, J=4.9 Hz, 2 H), 2.15 (s, 3 H), 1.06 (s, 9 H).

[0508] Preparation Example 17: Synthesis of compound I-17

[0509] Step 1: Synthesis of intermediate 17-1

[0510] Intermediate 16-1 (150 mg, 421.08 μmol) was dissolved in 50 mL of dichloromethane, and triethylamine (85.22 mg, 842.15 μmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (166.96 mg, 631.62 μmol) were added successively. The reaction system was stirred at 20 °C for 1 h. LCMS monitored the complete consumption of raw materials and the generation of product. The reaction liquid was concentrated to a residue under reduced pressure, and purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to obtain intermediate 17-1 as a white solid (150 mg, yield: 75.71%). 12g Silica Flash Column, flow phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to obtain intermediate 17-1 as a white solid (150 mg, yield: 75.71%). LCMS (ESI): m / z C 22 H 34 BrFNO2Si + [M+H] + Calcd = 470.15, 472.15 Found = 470.1, 472.1.

[0511] Step 2: Synthesis of intermediate 17-2

[0512] Intermediate 17-1 (510 mg, 1.08 mmol) was dissolved in 30 mL of acetonitrile, and a fluorinating agent (Selectfluor) (1.54 g, 4.34 mmol) was added. The reaction system was stirred at 20 °C for 1 h. The reaction liquid was concentrated to a residue under reduced pressure, and purified by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to obtain intermediate 17-2 as a white solid (510 mg, yield: 90.00%). 20g Intermediate 17-2 was prepared as a white solid (380 mg, yield: 94.02%) from Intermediate 17-1 using a Silica Flash Column, mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 30 mL / min) LCMS (ESI): m / z C 16 H 19 BrF2NO2 + [M+H] + Calc. = 374.06, 376.05 Found = 374.1, 376.0. 1 H NMR (400 MHz, CDC13) δ ppm 8.52 (s, 1 H), 7.78 (s, 1 H), 3.46 (t, J = 12.5 Hz, 2 H), 2.38 (s, 2 H), 2.31 (s, 3 H), 1.15 (s, 9 H).

[0513] Step 3: Synthesis of Intermediate 17-3

[0514] Intermediate 17-2 (380 mg, 1.02 mmol) was dissolved in 50 mL of ethanol, the reaction system was cooled to 0 °C, and sodium borohydride (115 mg, 3.06 mmol) was added. The reaction system was stirred at 25 °C for 1 hour. LCMS was used to monitor the consumption of raw materials. The reaction liquid was quenched with saturated ammonium chloride solution, and 100 mL of dichloromethane solution was added. After the organic phase was separated, it 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, which was subjected to silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to give Intermediate 17-3 as a white solid (300 mg, yield: 78.13%). 4g Intermediate 17-3 was prepared as a white solid (300 mg, yield: 78.13%) from Intermediate 17-2 using a Silica Flash Column, mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) LCMS (ESI): m / z C 16 H 21 BrF2NO2 + [M+H] + Calc. = 376.07, 378.07 Found = 376.1, 378.1.

[0515] Step 4: Synthesis of Intermediate 17-4

[0516] Intermediate 17-3 (380 mg, 1.01 mmol) was dissolved in 30 mL of dichloromethane, and triethylamine (2.04 g, 20.20 mmol) and methanesulfonic anhydride (703.76 mg, 4.04 mmol) were added. The reaction system was stirred at 0 °C for 1 h. TLC (petroleum ether: ethyl acetate = 4:1) monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was concentrated to a residue under reduced pressure, and column chromatography on silica gel (petroleum ether: ethyl acetate = 4:1) was performed to obtain intermediate 17-4 as a colorless oil (391 mg, yield: 85.21 %). LCMS (ESI): m / z C 20g Silica Flash Column, flow phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 17-4 as a colorless oil (391 mg, yield: 85.21 %). LCMS (ESI): m / z C 17 H 23 BrF2NO4S + .[M+H] + Calcd = 454.05, 456.05 Found = 454.0, 456.0.

[0517] Step 5: synthesis of intermediate 17-5

[0518] Intermediate 17-4 (300 mg, 660.32 µmol) was dissolved in 20 mL of DMSO, and sodium cyanoborohydride (41.50 mg, 660.32 µmol) was added. The reaction system was stirred at 90 °C for 1 h. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was diluted with 60 mL of water and extracted with dichloromethane (30 mL x 3). After the organic phase was separated, it was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a residue under reduced pressure. Column chromatography on silica gel (petroleum ether: ethyl acetate = 4:1) was performed to obtain intermediate 17-5 as a white solid (105 mg, yield: 44.14 %). LCMS (ESI): m / z C 12g Silica Flash Column, flow phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 25 mL / min) to obtain intermediate 17-5 as a white solid (105 mg, yield: 44.14 %). LCMS (ESI): m / z C 16 H 21 BrF2NO + .[M+H] + Calcd = 360.08, 362.08 Found = 360.0, 362.0.

[0519] Step 6: synthesis of compound I-17

[0520] With reference to the synthesis method of step 4 in preparation example 1, the corresponding raw material was replaced, and intermediate 17-5 was used as the raw material to prepare compound I-17 as a white solid. LCMS (ESI): m / z C25 H 30 F3N2O + .[M+H] + Calculated = 431.23 Found = 431.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (s, 1 H), 7.14 (t, J = 7.0 Hz, 1 H), 6.98 - 6.88 (m, 2 H), 6.83 (s, 1 H), 4.14 (s, 2 H), 3.40 (t, J = 14.4 Hz, 2 H), 3.33 - 3.21 (m, 4 H), 2.95 (t, J = 5.7 Hz, 2 H), 2.20 (s, 2 H), 2.19 (s, 3 H), 1.09 (s, 9 H).

[0521] Preparation 18: Synthesis of compound I-18a and compound I-18b

[0522] Step 1: Synthesis of intermediate 18-1

[0523] Compound 16-2 (800 mg, 2.24 mmol) was dissolved in 20 mL of dichloromethane, and triethylamine (1.12 g, 11.2 mmol) was added. The reaction system was cooled to 0 °C, and methanesulfonyl chloride (520 mg, 4.48 mmol) was slowly added dropwise. After the addition was completed, the system was stirred at 0 °C for 1 hour. LCMS monitoring showed that the raw material was completely consumed, and the product was generated. The reaction was quenched with 5 mL of water. After the organic phase was separated, it was washed with water (10 mL x 2), saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, to give intermediate 18-1 as a colorless oil (820 mg, crude). LCMS (ESI): m / z C 17 H 24 BrFNO4S + .[M+H] + Calculated = 436.06, 438.06 Found = 436.0, 438.0.

[0524] Step 2: Synthesis of intermediate 18-2

[0525] Intermediate 18-1 (820 mg, crude) was dissolved with 10 mL of DMSO, and sodium borohydride (254.21 mg, 6.72 mmol) was added. The reaction system was stirred at 35 °C for 1 hour. The raw material was monitored by LCMS to be completely reacted. The reaction solution was cooled to room temperature, quenched with 20 mL of 10% ammonium chloride solution, and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with water (5 mL x 2) and saturated brine (5 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 = 1:8) to give intermediate 18-2 as a white solid (550 mg). LCMS (ESI): m / z C 16 H 22 BrFNO + .[M+H] + Calc. = 342.09, 344.09 Found = 342.0, 344.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (s, 1H), 7.32 (s, 1H), 5.55-5.40 (m, 1H), 3.30-3.10 (m, 2H), 3.02 (m, 2H), 2.20 (s, 2H), 2.16 (s, 3H), 1.06 (s, 9H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 169.55, 139.86, 138.85, 135.68, 133.31, 131.52, 116.25, 94.93, 49.10, 42.46, 41.42, 31.03, 30.23, 18.00; 19 F NMR (376 MHz, DMSO-d6) δ ppm -158.55 (s, 1F).

[0526] Step 3: Synthesis of compounds I-18a and I-18b

[0527] Referring to the synthesis method of step 4 in Preparation Example 1, replacing the corresponding raw material, compound I-18 was prepared from intermediate 18-2 as a white solid. LCMS (ESI): m / z C 25 H 31 F2N2O + .[M+H] + Calc. = 413.24, Found = 413.2 1H NMR (400 MHz, CD3CN) δ ppm 7.69 (s, 1 H), 7.16 (t, J = 7.2 Hz, 1 H), 6.99-6.89 (m, 2 H), 6.80 (s, 1 H), 5.59-5.34 (m, 1 H), 4.29-4.05 (m, 2 H), 3.38-3.31 (m, 1 H), 3.29-2.89 (m, 7 H), 2.23 (s, 2 H), 2.21 (s, 3 H), 1.11 (s, 9 H).

[0528] Compound I-18 (140 mg) was further separated by chiral SFC, chiral preparation condition: chiral column DAICEL CHIRALPAK AD (size: 250 mm x 30 mm, particle size 10 μm), eluent CO2(A): isopropanol (B) containing 0.1% ammonia water, isocratic gradient (A / B = 55 / 45). Compound I-18a, the front peak, was obtained as a white solid (65 mg, ee value: 98%). Compound I-18b, the rear peak, was obtained as a white solid (60 mg, ee value: 99%). Chiral analysis condition: instrument Waters UPC C equipped with PDA detector and SQ detector, chiral column Chiralcel AD-3 (size: 50 mm x 4.6 mm, particle size 3 μm), eluent CO2(A): ethanol (B) containing 0.2% ammonia water, gradient: (A / B = 95 / 5 to 60 / 40, 1.5 min; maintain 60 / 40, 1 min; A / B = 95 / 5, maintain 0.5 min); flow rate 4 mL per minute, column temperature 35 °C; Compound I-18a, retention time: about 1.27 min; Compound I-18b, retention time: about 1.69 min.

[0529] Single crystal was cultivated by evaporation method: 0.5 mg of compound I-18a was dissolved in 1 mL of acetonitrile, and the system was slowly evaporated at room temperature to crystallize. X-ray single crystal diffraction was used, and the crystal system of compound I-18a belongs to monoclinic system, P21 space group, with cell parameters of α = 90°, β = 105.993(1)°, γ = 90°. The number of cell asymmetric units Z is 4, and the results of X-ray single crystal diffraction are shown in FIG. 1. It can be determined that the configuration of compound I-18a is S configuration as shown in the reaction formula, and the absolute configuration of compound I-18b can be deduced as R configuration as shown in the reaction formula.

[0530] Preparation Example 19: Synthesis of compounds I-19a and I-19b

[0531] Step 1: Synthesis of intermediate 19-1

[0532] Intermediate 15-2 (0.5 g, 1.48 mmol) was dissolved in 50 mL of methanol, 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 h. LCMS monitoring showed 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 solution. The reaction continued to stir for 30 min. 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 (Silica Flash Column, mobile phase gradient: 0-70% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to give intermediate 19-1 as a white solid (460 mg, yield: 91.34%). 20 g Silica Flash Column, flow phase gradient: 0-70% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to give intermediate 19-1 as a white solid (460 mg, yield: 91.34%). LCMS (ESI): m / z C 16 H 23 BrNO2 + [M+H] + Calcd = 340.09, 342.09 Found = 340.1, 342.1.

[0533] Step 2: Synthesis of intermediate 19-2

[0534] Intermediate 19-1 (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 h. LCMS monitoring showed that the raw material was completely consumed, 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 combined organic phase was washed with water (10 mL x 2), saturated brine (10 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 to give intermediate 19-2 as a light yellow solid powder (280 mg, yield: 65.83%). LCMS (ESI): m / z C 16 H 21 BrNO + [M+H] + Calcd = 322.08, 324.08 Found = 322.1, 324.1. 1H 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).

[0535] Step 3: Synthesis of intermediate 19-3

[0536] Dichloromethane (30 mL) was dissolved with diiodomethane (498.70 mg, 1.86 mmol), and 1.86 mL of diethyl zinc cyclohexane solution (1 M) was added sequentially at 0 °C. The reaction system was stirred at 0 °C for 30 min, and then a solution of intermediate 19-2 (200 mg, 620.66 μmol) in dichloromethane (3 mL) was added. The reaction system was stirred at 0 °C for 2.5 h. LCMS monitoring showed that the raw material was consumed completely and the product was generated. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to a residue, and the residue was prepared by silica gel column chromatography (Silica Flash Column, mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 100 mL / min) to obtain intermediate 19-3 as a white solid (200 mg, yield: 95.83%). 40g Silica Flash Column, flow phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 100 mL / min) to obtain intermediate 19-3 as a white solid (200 mg, yield: 95.83%). LCMS (ESI): m / z C 17 H 23 BrNO + [M+H] + Calculated = 336.10, 338.10 Found = 336.1, 338.2. 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).

[0537] Step 4: Synthesis of compounds I-19a and I-19b

[0538] Referring to the synthesis method of step 4 in preparation example 1, the corresponding raw material was replaced, and intermediate 19-3 was used as the raw material to prepare compound I-19 as a white solid. LCMS (ESI): m / z C 26 H 32 FN2O +[M+H] + Calcd. = 407.25 Found = 407.4. 1 H NMR (400 MHz, CD3CN) d ppm 7.74 (s, 1 H), 7.11 (t, J = 7.3 Hz, 1 H), 6.92 (d, J = 9.5 Hz, 2 H), 6.68 (s, 1 H), 4.08 (s, 2 H), 3.30-3.18 (m, 2 H), 3.13-3.07 (m, 1 H), 2.95-2.85 (m, 3 H), 2.36-2.27 (m, 1 H), 2.23 (s, 2 H), 2.15 (s, 3 H), 1.86-1.77 (m, 1 H), 1.15-1.09 (m, 9 H), 1.02-0.97 (m, 1 H), -0.05--0.08 (m, 1 H). Compound I-19 (40 mg) was further separated by chiral SFC, chiral prep condition: chiral column DAICEL CHIRALPAK AD (size: 250 mm x 30 mm, particle size 10 pm), eluent CO2(A): isopropanol (B) containing 0.1% ammonia water (A / B = 70 / 30) isocratic. Compound I-19a, front peak, was obtained as a white solid (16 mg, ee value: 98%). Compound I-19b, back peak, was obtained as a white solid (15 mg, ee value: 98%). Chiral analysis condition: instrument Waters UPC C with PDA detector and SQ detector, chiral column Chiralcel AD-3 (size: 50 mm x 4.6 mm, particle size 3 pm), eluent CO2(A): ethanol (B) containing 0.2% ammonia water, gradient: (A / B = 95 / 5 to 60 / 40, 1.5 min; maintain 60 / 40, 1 min; A / B = 95 / 5, maintain 0.5 min); flow rate 4 mL per minute, column temperature 35 °C; Compound I-19a, retention time: about 1.1 min; Compound I-19b, retention time: about 1.32 min.

[0539] Preparation Example 20: Synthesis of compounds I-20a and I-20b

[0540] Step 1: Synthesis of intermediate 20-2

[0541] Referring to the synthesis method of step 1 and step 2 in Preparation Example 15, replacing the corresponding raw materials, intermediate 20-2 was prepared from intermediate 5-1 as a white solid. LCMS (ESI): m / z C 16 H 19 BrNO2 + [M+H] + Calcd. = 407.25 Found = 407.4. Calcd. = 407.25 Found = 407.4.1 H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (s, 1 H), 7.79 (s, 1 H), 2.98 - 2.85 (m, 2 H), 2.66 (dd, J=6.9 Hz, 4.8 Hz, 2 H), 2.27 (s, 2 H), 2.17 (s, 3 H), 1.15 (s, 3 H), 0.56 (s, 2 H), 0.31 (t, J=4.8 Hz, 2 H); 13 CNMR (101 MHz, DMSO-d6) δ ppm 204.48, 170.16, 152.98, 139.17, 136.68, 133.86, 132.95, 118.15, 45.33, 37.00, 26.12, 23.81, 17.69, 14.17, 12.95.

[0542] Step 2: Synthesis of intermediate 20-4

[0543] Referring to the synthesis method of step 1 and step 2 in Preparation Example 16, the corresponding raw materials were replaced, and intermediate 20-4 was prepared from intermediate 20-2 as a white solid. LCMS (ESI): m / z C 16 H 20 BrFNO2 + [M+H] + Calculated = 356.07, 358.06 Found = 356.0, 358.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (s, 1 H), 7.40 (s, 1 H), 5.33 (d, J=6.8 Hz, 1 H), 5.15 - 5.00 (m, 2 H), 3.10 - 2.91 (m, 2 H), 2.24 (s, 2 H), 2.16 (s, 3 H), 1.15 (s, 3 H), 0.54 (d, J=4.8 Hz, 2 H), 0.32 (d, J=3.4 Hz, 2 H); 13 CNMR (101 MHz, DMSO-d6) δ ppm 170.07, 140.13, 137.55, 137.51, 136.34, 133.94, 132.96, 116.51, 94.20, 74.81, 45.36, 37.51, 37.29, 23.81, 18.03, 14.30, 13.12; 19 FNMR (376 MHz, DMSO-d6) δ ppm -185.35 (s, 1 F).

[0544] Step 3: Synthesis of compound I-20a and I-20b

[0545] Preparation 18, intermediate 20-4 was used as starting material to prepare intermediate I-20 as a white solid. LCMS (ESI): m / z C 25 H 29 F2N2O + [M+H] + Calcd = 411.22 Found = 411.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1 H), 7.30 - 7.12 (m, 1 H), 7.07 - 6.94 (m, 2 H), 6.76 (s, 1 H), 5.65 - 5.35 (m, 1 H), 4.27 - 4.01 (m, 2 H), 3.30 - 3.27 (m, 1 H), 3.26 - 2.79 (m, 7 H), 2.20 (s, 2 H), 2.16 (s, 3 H), 1.16 (s, 3 H), 0.58 - 0.51 (m, 2 H), 0.41 - 0.29 (m, 2 H).

[0546] Compound I-20 (150 mg) was further separated by chiral SFC, chiral preparation condition: chiral column DAICEL CHIRALPAK AD (size: 250 mm x 30 mm, particle size 10 pm), eluent CO2(A): isopropanol (B) containing 0.1% ammonia water (B), isocratic gradient (A / B = 50 / 50). Compound I-20a, the front peak, was obtained as a white solid (72 mg, ee value: 99%). Compound I-20b, the back peak, was obtained as a white solid (73 mg, ee value: 99%). Chiral analysis condition: instrument Waters UPC C with PDA detector and SQ detector, chiral column Chiralcel AD-3 (size: 50 mm x 4.6 mm, particle size 3 pm), eluent CO2(A): ethanol (B) containing 0.2% ammonia water (B), gradient: (A / B = 95 / 5 to 60 / 40, 1.5 min; maintain 60 / 40, 1 min; A / B = 95 / 5, maintain 0.5 min); flow rate 4 mL per minute, column temperature 35 °C; Compound I-20a, retention time: about 1.16 min; Compound I-20b, retention time: about 1.58 min.

[0547] Preparation 21 : Synthesis of compounds I-21a and I-21b

[0548] Step 1 : Synthesis of intermediate 21-2

[0549] Reference to the synthetic method of step 3 in Preparation 19, intermediate 21-1 was used as starting material to prepare intermediate 21-2 as a colorless oil. 1H NMR (400 MHz, CDC13) δ ppm 7.10 (dd, J=3.3, 7.6 Hz, 2 H), 6.92 - 6.78 (m, 1 H), 3.06 - 2.94 (m, 1 H), 2.89 - 2.78 (m, 1 H), 2.42 - 2.20 (m, 1 H), 1.84 - 1.67 (m, 1 H), 0.99 - 0.94 (m, 1 H), 0.07 - 0.07 (m, 1 H).

[0550] Step 2: Synthesis of intermediate 21-3

[0551] With reference to the synthesis method of Step 1 in Preparation Example 1, the corresponding raw material was replaced, and intermediate 21-3 was prepared from intermediate 21-2 as a light yellow oil. LCMS (ESI): m / z C 11 H 12 NO2 + [M + H] + Calculated = 190.09, Found = 190.1.

[0552] Step 3: Synthesis of intermediate 21-4

[0553] Intermediate 21-3 (3 g, 12.23 mmol) was dissolved in 10 mL of acetonitrile, and N-bromosuccinimide (2.18 g, 12.23 mmol) was added. The reaction system was stirred at 20 °C for 2 hours. LCMS monitoring showed that the raw material was consumed completely, and the product was generated. The reaction liquid was quenched with 5% aqueous sodium sulfite solution (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, 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 (40 g 40g Silica Flash Column, mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 50 mL / min) to obtain intermediate 21-4 as a white solid (3.5 g, yield: 88.28%). LCMS (ESI): m / z C 11 H 11 BrNO2 + [M + H] + Calculated = 268.00, 270.00, Found = 268.0, 270.0.

[0554] Step 4: Synthesis of intermediate 21-5

[0555] With reference to the synthesis method of Step 2 in Preparation Example 1, the corresponding raw material was replaced, and intermediate 21-5 was prepared from intermediate 21-4 as a colorless oil. LCMS (ESI): m / z C 10H 11 BrN + .[M+H] + Calcd = 224.01, 226.01 Found = 224.0, 226.0.

[0556] Step 5: Synthesis of intermediate 21-6

[0557] Referring to the synthetic method of step 2 in Preparation Example 6, replacing the corresponding raw material, intermediate 21-6 was prepared from compound 21-5 as a light brown solid. LCMS (ESI): m / z C 10 H 10 BrIN + .[M+H] + Calcd = 349.90, 351.90 Found = 349.9, 351.8. 1 H NMR (400 MHz, CDC13) δ ppm 7.55 (s, 1 H), 4.48 - 3.43 (m, 2 H), 3.09 - 2.93 (m, 1 H), 2.90 - 2.77 (m, 1 H), 2.53 - 2.32 (m, 1 H), 1.97 - 1.80 (m, 1 H), 1.17 - 1.12 (m, 1 H), 0.22 - 0.09 (m, 1 H).

[0558] Step 6: Synthesis of intermediate 21-8

[0559] Referring to the synthetic method of step 2 and step 3 in Preparation Example 10, replacing the corresponding raw material, intermediate 21-8 was prepared from compound 21-6 as a white solid. LCMS (ESI): m / z C 17 H 23 BrNO + .[M+H] + Calcd = 336.10, 338.10 Found = 335.9, 337.9. 1 H NMR (400 MHz, CDC13) δ ppm 7.17 (s, 1 H), 6.54 (s, 1 H), 3.14 (dd, J=6.8, 17.3 Hz, 1 H), 3.03 - 2.87 (m, 1 H), 2.48 - 2.44 (m, 1 H), 2.24 (s, 2 H), 2.17 (s, 3 H), 1.89 - 1.80 (m, 1 H), 1.13 (s, 9 H), 1.11 - 1.08 (m, 1 H), 0.19 - 0.16 (m, 1 H).

[0560] Step 7: Synthesis of compound I-21a and I-21b

[0561] Compound I-21 was prepared according to the procedure described in Step 4 of Preparation 1, by replacing the corresponding starting material with intermediate 21-8, as a white solid. LCMS (ESI): m / z C 26 H 32 FN2O + [M+H] + Calculated = 407.25 Found = 407.2. 1 H NMR (400 MHz, CD3CN) δ ppm 7.49 (s, 1 H), 7.16 (t, J = 7.1 Hz, 1 H), 7.02 - 6.86 (m, 2 H), 6.67 (s, 1 H), 4.34 (d, J = 15.1 Hz, 1 H), 4.14 - 4.07 (m, 1 H), 3.75 - 3.67 (m, 1 H), 3.18 - 3.16 (m, 1 H), 3.12 - 2.86 (m, 3 H), 2.84 - 2.75 (m, 1 H), 2.35 - 2.27 (m, 1 H), 2.17 (s, 2 H), 2.13 (s, 3 H), 1.89 - 1.80 (m, 1 H), 1.20 - 1.14 (m, 1 H), 1.09 (s, 9 H), 0.04 - 0.01 (m 1 H).

[0562] Compound I-21 (200 mg) was further separated by chiral SFC, chiral preparation condition: chiral column DAICEL CHIRALCEL OD (size: 250 mm x 30 mm, particle size 10 μm), eluent CO2(A): ethanol (B) containing 0.1% ammonia water, isocratic (A / B = 70 / 30). Compound I-21a, the front peak, was separated as a white solid (85 mg, ee value: 98%). Compound I-21b, the back peak, was separated as a white solid (86 mg, ee value: 100%). Chiral analysis condition: instrument Waters UPC C equipped with PDA detector and SQ detector, chiral column Chiralcel OD-3 (size: 50 mm x 4.6 mm, particle size 3 μm), eluent CO2(A): ethanol (B) containing 0.2% ammonia water, gradient: (A / B = 95 / 5 to 60 / 40, 1.5 min; maintain 60 / 40, 1 min; A / B = 95 / 5, maintain 0.5 min); flow rate 4 mL per minute, column temperature 35 °C; Compound I-21a, retention time: about 1.01 min; Compound I-21b, retention time: about 1.17 min.

[0563] Single crystal was cultivated by evaporation method: 0.5 mg of compound I-21a was dissolved in 1 mL of acetonitrile, and the system was slowly evaporated at room temperature to crystallize. By X-ray single crystal diffraction, compound I-21a belongs to monoclinic crystal system, P21 space group, and the cell parameters are a = 90°, b = 104.071(4)°, g = 90°. The unit cell asymmetric unit number Z is 2, and the results of X-ray single crystal diffraction are shown in Figure 2. It can be determined that the configuration of compound I-21a is as shown in the reaction formula, and the two chiral centers are both R configuration. Therefore, the absolute configuration of compound I-21b can be deduced as shown in the reaction formula, and the two chiral centers are both S configuration.

[0564] Biological test example 1: Patch clamp detection of the effect of compounds on KCNQ2 / 3 potassium channel current

[0565] 1. Purpose of the test: using HEK-293 cell line stably expressing human KCNQ2 / 3 channel, to evaluate the effect of the compound of the present application on the opening activity of KCNQ2 / 3 channel.

[0566] 2. Test method:

[0567] Cell culture: HEK-293 cell line stably expressing human KCNQ2 / 3 channel (HEK-293 cell source ATCC) was cultured in DMEM medium containing 10% fetal bovine serum, the culture temperature was 37°C, and the carbon dioxide concentration was 5%.

[0568] 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).

[0569] Compound administration and patch clamp detection: before patch clamp detection, the cells were separated with 0.25% Trypsin-EDTA, and 8 x 10 3 cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, administration and patch clamp detection were performed.

[0570] When the amplitude of current is stable in control extracellular solution, the drug is given. The control extracellular solution and the working solution of the compound to be tested (a certain amount of the test substance is dissolved in DMSO and diluted to 0.2 mM, and then the test substance is diluted with the extracellular solution to prepare a working solution of 0.2 μM, which is ultrasonicated for 20 min without visible precipitate) are made to flow through the recording bath by gravity perfusion so as to act on the cells, while liquid displacement is performed by using a peristaltic pump in the recording. All electrophysiological tests are performed at room temperature.

[0571] 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;

[0572] 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;

[0573] The voltage stimulation protocol for recording the KCNQ2 / 3 channel current by whole-cell patch clamp is as follows: after the whole-cell patch is formed, the membrane voltage of the cell is clamped at -80 mV. The clamping voltage is maintained at -120 mV for 3 s, and then is depolarized to +40 mV at a step of 10 mV, and the mean steady-state current is used for IV curve analysis; then the current is continuously recorded at a voltage of -30 mV for 500 ms, and the peak tail current is used for activation curve analysis.

[0574] 3. Data analysis:

[0575] First, the IV curve is plotted with the step voltage as the horizontal axis and the normalized current as the vertical axis, and then the relative current size after the action of the compound at a voltage of -30 mV is compared and the fold increase of the current amplitude after the action of the compound relative to the current amplitude without drug is calculated. Activation%=(Icompound / Icontrol)*100%.

[0576] The activation curve is fitted by the Boltzmann equation from the peak tail current, i.e. I / Imax=1 / (1+exp((V 1 / 2 -Vm) / к)), wherein I / Imax is the normalized tail current, V 1 / 2half-activation voltage, Vm is the test voltage, k is a correlation factor for the slope factor of the activation curve, and ΔV 1 / 2 = V 1 / 2 test-V 1 / 2 control formula (V 1 / 2 test represents the half-activation voltage V 1 / 2 , V 1 / 2 control represents V 1 / 2 for the same cell without administration of the compound) to calculate the V 1 / 2 left shift amplitude.

[0577] 4. Test results: see Table 1.

[0578] Table 1. Effect of compounds on KCNQ2 / 3 potassium channel current

[0579] The compound of formula I' of the present application has good opening activity on KCNQ2 / 3 channel, significantly enhances the KCNQ2 / 3 channel current, and the half-activation voltage is significantly left shifted, which is superior to XEN-1101.

[0580] Biological test example 2: patch clamp detection of the effect of compounds on KCNQ4, KCNQ5 potassium channel current

[0581] 1. Purpose of the test: using HEK293 cell lines stably expressing human KCNQ4 or transiently expressing KCNQ5 channels, to evaluate the effect of the compounds of the present application on the opening activity of KCNQ4, KCNQ5 channels.

[0582] 2. Test method:

[0583] Culture and passage of HEK293 cells stably expressing KCNQ4: HEK293 cell lines stably expressing human KCNQ4 (NM_004700) channels were cultured in DMEM medium containing 10% fetal bovine serum, the culture temperature was 37℃, 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℃ for about 1 min. When the cells are detached from the bottom of the dish, add about 5 mL of 37℃ preheated complete culture medium. The cell suspension is gently blown with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube, centrifuge at 1000 rpm for 5 min to collect the cells. Expand or maintain the culture, inoculate the cells in a 6 cm cell culture dish, and inoculate the cells in each cell culture dish at a cell amount of 2.5×10 5Cells (final volume: 5 mL). Cells were detached with 0.25% Trypsin-EDTA before patch clamp test, 7 x 10 3 cells were plated onto coverslips in 24-well plates (final volume: 500 μL) and incubated for 18 hours before dosing and test.

[0584] HEK293 cell culture and transfection for transient expression of KCNQ5 (NM_019842): HEK-293 cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C with 5% CO2.

[0585] Day 1: Cells were seeded into 6-well plates at 5 x 10 5 cells per well.

[0586] Day 2: Transfection was performed using Invitrogen Lipofectamine TM 3000 transfection reagent, with a plasmid to transfection reagent ratio of 1 μg:2 μL. The total amount of plasmid used per well was 3 μg. Specifically, two sterile centrifuge tubes were used, each containing 100 μL Opti-MEM TM , one of which contained 6 μL Lipofectamine 3000 and the other 3 μg plasmid. The plasmid was mixed with 6 μL P3000 TM , and then the diluted plasmid DNA was added to the diluted Lipofectamine 3000 and incubated at room temperature for 10-15 min. The DNA-liposome complex was added dropwise to the cells, mixed gently, and incubated in the incubator. The medium was changed after 4-6 hours.

[0587] Day 3: Cells were digested and seeded into 24-well plates with coverslips at 8 x 10 3 cells per well.

[0588] Day 4: Dosing and patch clamp test were performed.

[0589] Compound dosing and patch clamp test: After the current amplitude of the cells in the control extracellular solution was stable, dosing 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) were allowed to flow through the recording bath to act on the cells by gravity perfusion, while liquid displacement was performed by a peristaltic pump during recording. All electrophysiological tests were performed at room temperature.

[0590] 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;

[0591] 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;

[0592] The voltage protocol for recording KCNQ potassium currents in whole-cell patch clamp configuration was as follows: after forming the whole-cell seal, the cell membrane was held at -80 mV. The holding voltage was stepped from -120 mV to +40 mV in 10 mV steps for 3 s, and the mean steady-state current was used for IV curve analysis; then a 500 ms recording was made at -30 mV, and the peak tail current was used for activation curve analysis.

[0593] 3. Data analysis:

[0594] 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 compound was added at -30 mV was compared, and the fold increase in current amplitude after the compound was added relative to the current amplitude without administration was calculated, Activation% = (Icompound / Icontrol)*100%.

[0595] The activation curve was fitted by the Boltzmann equation from the peak 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 ΔV 1 / 2 = V 1 / 2 test-V 1 / 2 control, where V 1 / 2 test represents the half-activation voltage V 1 / 2 after administration, and V 1 / 2 control represents V 1 / 2 for the same cell without administration. 1 / 2 Left shift amplitude.

[0596] 4. Test results: see Table 2.

[0597] Table 2. Effects of compounds on KCNQ4, KCNQ5 potassium channel currents

[0598] NA: not detectable

[0599] The compound of Formula I' of the present application has relatively weak opening degree on KCNQ4 and KCNQ5, and the selectivity on KCNQ2 / 3 is significantly improved compared with XEN-1101, and is expected to have small toxic side effects in vivo.

[0600] Biological test example 3: protective effect of compounds on pentyltetrazole (PTZ)-induced mouse epilepsy model

[0601] 1. Purpose of the test:

[0602] The protective effect of the compound of the present application on PTZ-induced seizures was evaluated using a male KM mouse seizure model induced by pentyltetrazole (PTZ).

[0603] 2. Test animals:

[0604] Male KM mice weighing 18-24 g were selected, and the animals were purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0605] 3. Test method:

[0606] Before the test, the animals were randomly divided into groups according to their body weight, with 6 animals in each group. According to the "3R" principle of animal experiments, 3 animals were preferentially administered at a starting dose of 5 mg / kg. If the proportion of V-stage seizures in the 3 animals was greater than 50%, it was considered that the protective effect was general, and no further animal administration was performed. Otherwise, the remaining 3 mice were administered, and if none of the 6 animals had seizures, no higher dose administration was performed. Otherwise, administration at a dose of 10 mg / kg was continued. At the beginning of the test, the test compound was administered by gavage at a dose of 5 mg / kg or 10 mg / kg, with the vehicle being 10% DMSO + 10% solutol + 80% physiological saline, at a concentration of 0.5 mg / mL or 1 mg / mL, and the administration volume being 10 mL / kg. One hour later, seizures were induced by subcutaneous injection of 80 mg / kg of PTZ, with the injection volume being 10 mL / kg and the concentration being 8 mg / mL. The number of clonic and tonic seizures within 1 hour after PTZ injection, the time, and the death were observed. According to Table 3, the protective effect of the compound on PTZ-induced seizures in mice was evaluated based on the proportion of V-stage seizures after administration (V-stage seizure proportion % = number of V-stage seizure animals / total number of test animals * 100).

[0607] Table 3. Classification of seizures

[0608] 4. Test results: see Table 4.

[0609] Table 4. Effect of different compounds on the proportion of PTZ-induced V grade seizures

[0610] The compound of Formula I' of the present application has a significant protective effect on PTZ-induced V grade seizures in mice. In addition, I-2 has a certain protective effect at 1 mg / kg, but mice show symptoms such as convulsions at more than 3 mg / kg, and the side effects are greater.

[0611] Biological test example 4: Effect of compounds on the motor balance and coordination ability of mice

[0612] 1. Purpose of the test:

[0613] The rotarod test was used to evaluate the effect of the compounds of the present application on the motor balance and coordination ability of male KM mice.

[0614] 2. Test animals:

[0615] KM mice, 18-24 g, purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0616] 3. Test method:

[0617] The day before the test, all mice were pre-trained. The rotarod fatigue instrument was set to rotate at 6 rpm, and only mice that stayed 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 start of the test, 15-60 mg / kg of the test compound was administered orally, and the solvent was 10% DMSO+10% solutol+80% physiological saline; the drug was administered orally according to the body weight of the mice, and the administration volume was 10 mL / kg.

[0618] 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 rods of the fatigue instrument in turn, and after observing that the mice could move stably on the rotating rods for at least 2 seconds, the Run button was clicked to start timing. The time for the mice to fall off the rotating rods was recorded, and the test was performed for 3 times in succession. If the mice did not fall off after 60 seconds, 60 seconds was counted as the falling time. According to the percentage of animals falling off the rotating rods (the number of animals falling off within 60 seconds / number of test animals*100%), a four-parameter Logistic regression model was used to calculate the TD 50 .

[0619] 4. Test results: see Table 5.

[0620] Table 5. Effect of compounds on the motor balance and coordination ability of mice (TD50 )

[0621] The compound of Formula I' has no significant effect on the motor balance and coordination of mice, and the safety window is better than that of XEN-1101. The highest dose of I-18a up to 180 mg / kg also has no significant effect on the motor balance and coordination of mice.

[0622] Biological test example 5: Study on the absorption and blood-brain barrier penetration ability of the compound

[0623] 1. Purpose of the test:

[0624] To evaluate the absorption and blood-brain barrier penetration ability of the compound of the present application.

[0625] 2. Test animals

[0626] KM mice, 18-24 g, purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0627] 3. Test method:

[0628] KM mice, according to the body weight, 5 mg / kg of the compound of the present application was administered by gavage, 3 mice in each group, vehicle: 10% DMSO + 10% solutol + 80% normal saline, the volume of administration was 10 mL / kg; and at the 2h time point after administration, at least 0.5 mL of whole blood was collected into an EDTA-K2 anticoagulation tube, within half an hour, the blood plasma was separated by centrifugation (6000 r / min, 8 min, 4°C), and stored at -80°C for standby. At the same time, the brain tissue was collected, washed with normal saline and dried with absorbent paper, weighed, and stored at -80°C for standby.

[0629] HPLC-MS / MS was used to analyze the concentration of the compound in the plasma and brain tissue samples.

[0630] Test results: see Table 6.

[0631] Table 6. Concentration of brain and blood of KM mice 2h after single oral administration

[0632] The compound of Formula I' has good absorption and brain penetration ability (B / P>0.8), and the 2h plasma and brain tissue concentrations are significantly higher than those of XEN-1101.

[0633] Biological test example 6: Protective effect of the compound on the maximum electric shock (MES) induced mouse tonic seizure model

[0634] 1. Purpose of the test:

[0635] The protective effect of the compound of the present application on the MES-induced convulsive seizures of mice is evaluated by using the maximal electro shock model (MES model).

[0636] 2. Test animals:

[0637] Male KM mice weighing 18-25 g are selected, and the animals are purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd.

[0638] 3. Test method:

[0639] Before the test, the animals are randomly grouped according to the body weight, with 6 animals in each group. At the beginning of the test, the animals are respectively given 6 mg / kg of the test compound (solvent preparation) or solvent by gavage according to the body weight, with the administration volume being 10 mL / kg, and the solvent being 10% DMSO+10% Solutol+80% physiological saline. At 6 h after the administration, the auricular electrodes are wetted with physiological saline, clamped on the ears of the animals, and the animals are electrically shocked by using an electroshock instrument (60 Hz, 0.3 ms, 1 s, 45 mA). Whether the animals have convulsive seizures is observed and recorded, and the protective effect of the compound on the MES-induced convulsive seizures of mice is evaluated by the protection rate of the animals against the MES-induced convulsive seizures after the administration. The convulsive seizure protection rate (%) = (1- the number of animals with convulsive seizures / the number of test animals) * 100. Z

[0640] 4. Test results: see Table 7.

[0641] Table 7. Convulsive seizure protection rate of the compound against the MES-induced seizures of mice after the administration

[0642] The compound of Formula I' has a good protective effect on the MES-induced convulsive seizures of mice, and the effect is significantly better than that of XEN-1101.​

Claims

1. A compound I’ or a pharmaceutically acceptable salt thereof, wherein n' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each R 1 each independently D, -OH, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogen; Ring A is wherein represents that ring A forms a ring with phenyl through the bond; p is 1 or 2; q is 0, 1, 2, 3, 4, 5, or 6; each R 2 each independently D, -OH, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 2-1 substituted C1-C6alkyl; or two R groups located on adjacent carbons 2 together with the carbon atoms to which they are directly attached form a three-membered saturated carbocyclic ring, which is optionally substituted with 1 or 2 R 2-2 groups; each R 2-1 each independently D or halogen; each R 2-2 each independently D or halogen; L' is a bond, -O- or -(CR L 2) m -; each R L each independently H or D; m is 1 or 2; 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, Ci-C6alkyl, or -Si(Ci-C6alkyl)3; each R 3-2 each independently D or halogen; R 4 is methyl or methyl substituted with 1-3 D.

2. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound is Compound I, 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; Ring A is wherein represents that ring A forms a ring with phenyl through the bond; p is 1 or 2; q is 0, 1, 2, 3, 4, 5, or 6; each R 2 each independently D, -OH, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more R 2-1 substituted C1-C6alkyl; or two R groups located on adjacent carbons 2 together with the carbon atoms to which they are directly attached form a three-membered saturated carbocyclic ring, which is optionally substituted with 1 or 2 R 2-2 groups; each R 2-1 each independently D or halogen; each R 2-2 each independently D or halogen; L is a chemical bond, -O- or -(CH2) m -; m is 1 or 2; 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, Ci-C6alkyl, or -Si(Ci-C6alkyl)3; each R 3-2 each independently D or halogen; R 4 is methyl or methyl substituted with 1-3 D.

3. The compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, which satisfy one or more of the following conditions: (1) R 1 In the above-mentioned groups, the halogen and the halogen in the C1-C6alkyl group substituted by one or more halogens are each independently fluorine, chlorine, bromine or iodine, preferably fluorine. R 1 In the above, the halogen and the halogen in the C1-C6 alkyl substituted with one or more halogens are each independently fluorine, chlorine, bromine or iodine, preferably fluorine. (2) R 1 each independently of one another in each occurrence in the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, preferably methyl; R 1 In particular, each of the C1-C6-alkyl, the C1-C6-alkyl in -O-C1-C6-alkyl, the C1-C6-alkyl in C1-C6-alkyl substituted by one or more halogens, the C1-C6-alkyl in C1-C6-alkyl substituted by one or more halogens is independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, preferably methyl. (3) R 2 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (4) R 2 C1-C6alkyl, -O-C1-C6alkyl, C1-C6alkyl in -O-C1-C6alkyl substituted by one or more R 2-1 each independently is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, preferably methyl; (5) R 2-1 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (6) R 2-2 In particular, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine. (7)R 3 In the context, the C1-C6 alkyl group, with one or more R 3-2 The C1-C6 alkyl group in the substituted C1-C6 alkyl group and the C1-C6 alkyl group in -Si(C1-C6 alkyl)3 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or tert-butyl; (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-C6 alkyl group in the group -C(=0)R10and the C1-C6 alkyl group in the group -S(0)2R10are each independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a 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 In the methyl substituted with 1-3 D, the methyl substituted with 1, 2 or 3 D is meant. (13) the 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.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein, which satisfy one or more of the following conditions: (1) n' is 0, 1, 2, 3, 4, 5, 6, or 7; preferably 0, 1, 3, 5, or 7, more preferably 0 or 1; n is 0 or 1; (2) each R 1 each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogen; preferably, each R 1 each independently D, -OH, or halogen (e.g., F); each R 1 each independently halogen, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogens; (3) Ring A is o is 0, 1 or 2, each R 2 each independently D, -OH, halogen, C1-C6alkyl, -O-C1-C6alkyl, or substituted C1-C6alkyl; preferably 2-1 each independently D, -OH, halogen, C1-C6alkyl, -O-C1-C6alkyl, or substituted C1-C6alkyl; preferably o is 0, 1 or 2, each R 2 each independently D, -OH or halogen; more preferably each R 2 each independently -OH or fluoro; (4) q is 0, 1, or 2; (5) each R 2-1 each independently halogen; (6) each R 2-2 each independently halogen; (7) L' is -O-, -(CH2) m - or -(CD2) m -, m is 1 or 2; preferably, L' is -O- or -(CH2) m -, m is 1 or 2; L is -O- or -(CH2) m - and m is 1 or 2; (8) R 3 C1-C6 alkyl, C3-C8 cycloalkyl which is substituted by one or more R 3-1 substituted with one or more R 3- 2 substituted with one or more R 3-1 substituted with one or more R 3-1 substituted with one or more R (9) each R 3-1 each independently C1-C6alkyl; (10) each R 3-2 each independently D or halogen; preferably, each R 3-2 each independently halogen; (11) R 4 is methyl or methyl substituted with 3 D; (12) 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 halogens; k is 0, 1, 2, or 3 (preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2 each independently D, -OH, -CN, halogen (e.g., fluorine), C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogens (preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH); (13) For wherein n is 0 or 1 ; R 1 is D, -CN, halogen, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogens.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, which satisfy one or more of the following conditions: (1) n' is 1; n is 1; (2) each R 1 each independently D or halogen; preferably fluorine; each R 1 each independently halogen; preferably fluorine; (3) Ring A is (For example )、 (For example )、 (For example )、 (For example )、 (4) q is 0 or 1; (5) each R 2 each independently fluorine; (6) each R 2-2 each independently fluorine; (7) L' is -O-, -CH2-, or -CD2, preferably -CH2-; L is -O- or -CH2-, preferably -CH2-; (8) R 3 is tert-butyl, ethyl, preferably tert-butyl, ethyl, more preferably tert-butyl, Further preferred is tert-butyl or (9) each R 3-1 each independently C1-C3alkyl; preferably methyl; (10) each R 3-2 each independently fluorine or D; preferably, each R 3-2 each independently fluorine; (11) R 4 is methyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein, The compound is compound I-1’, I-2’, I-3’ or I-4’: wherein o is 0, 1 or 2, n', R 1 ', R 2 , q, R 2-2 , L', R 3 and R 4 are as defined in any one of claims 1-5; Preferably, the compound is any one of the following: (1) in compounds I-1' and I-2', n' is 0, 1, 2, 3, 4, 5, 6, or 7; each R 1 each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; q is 0, 1, or 2; each R 2 each independently D, -OH, or halogen; L' is -0-, -(CH2) m - or -(CD2) m - and m is 1 or 2; R 3 C3-C8cycloalkyl substituted by one or more R 3-1 Ci-C6alkyl, C3-C8cycloalkyl substituted by one or more R 3-2 Ci-C6alkyl; R 3-1 is C1-C3 alkyl; R 3-2 is D or halogen; R 4 is methyl or methyl substituted with 1-3 D; Preferably, For wherein n is 0, 1, 2, or 3, each R 1 each independently D, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; k is 0, 1, 2, or 3 (more preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2 each independently D, -OH, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH); (2) in compounds I-3' and I-4', n' is 0, 1, 2, 3, 4, 5, 6, or 7; each R 1 each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; o is 0 or 2; each R 2-2 each independently halogen, preferably F; L' is -0-, -(CH2) m - or -(CD2) m -; preferably -0- or -(CH2) m -; m is 1 or 2; R 3 C3-C8cycloalkyl substituted by one or more R 3-1 C3-C8cycloalkyl substituted by one or more R 3-2 C3-C8cycloalkyl substituted by one or more R R 3-1 Ci-C3-alkyl; R 3-2 is D or halogen; R 4 is methyl or methyl substituted with 1-3 D; Preferably, For wherein n is 0, 1, 2, or 3, each R 1 each independently D, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; k is 0, 1, 2, or 3 (more preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2 each independently D, -OH, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH).

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein, The compound is compound I-1, I-2, I-3, or I-4: wherein o is 0, 1 or 2, n, R 1 , R 2 , q, R 2-2 , L and R 3 are as defined in any one of claims 1 to 6; Preferably, the compound is any one of the following: (1) in compounds I-1 and I-2, n is 0 or 1; each R 1 each independently halogen, -O-C1-C6alkyl, or C1-C6alkyl substituted with one or more halogens; q is 0, 1, 2; each R 2 each independently D, -OH, or halogen; L is -O- or -(CH2) m - and m is 1 or 2; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; (2) in compounds I-3 and I-4, n is 0 or 1; each R 1 each independently halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; o is 0 or 2; each R 2-2 each independently halogen, preferably F; L is -O- or -(CH2) m - and m is 1 or 2; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; More preferably, the compound is any one of the following: (1) in compound I-1, n is 1; R 1 is halogen; preferably F; q is 0, 1, 2; each R 2 each independently -OH or halogen; L is O or -CH2-; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; (2) in compound I-2, n is 1; R 1 is halogen; preferably F; q is 0; L is -CH2-; R 3 C1-C6-alkyl or C3-C8-cycloalkyl, each of which is optionally substituted by one or more R 3-1 substituted C3-C8-cycloalkyl; R 3-1 is C1-C3 alkyl; (3) in compounds I-3 and I-4, n is 1; R 1 is halogen; preferably F; o is 0 or 2; each R 2-2 each independently halogen, preferably F; L is -CH2-; R 3 is Ci-C6-alkyl; preferably tert-butyl; Further more preferably, the compound is any one of the following: (1) in compound I-1, n is 1; R 1 is halogen; preferably F; q is 0 or 1; R 2 is halogen; preferably F; L is -CH2-; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 It is a C1-C3 alkyl group; preferably, R 3 For tert-butyl, (2) in compounds I-3 and I-4, n is 1; R 1 is halogen; preferably F; o is 0; L is -CH2-; R 3 is Ci-C6-alkyl; preferably tert-butyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, The compound is compound I-1-1’, I-1-2’ (e.g. I-1-2-1’ or I-1-2-2’), I-3-1’ (e.g. I-3-1-1’ or I-3-1-2’), or I-4-1’ (e.g. I-4-1-1’ or I-4-1-2’): (e.g. ) (e.g. ) or (e.g. ), wherein o is 0, 1 or 2, n', R 1 ', R 2 , R 2-2 , L', R 3 and R 4 are as defined in any one of claims 1-7; Preferably, the compound is any one of the following: (1) in compound I-1-1', n' is 0, 1, 2, 3, 4, 5, 6, or 7; each R 1 each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; L' is -0-, -(CH2) m - or -(CD2) m - and m is 1 or 2; R 3 C3-C8cycloalkyl substituted by one or more R 3-1 C3-C8cycloalkyl substituted by one or more R 3-2 C3-C8cycloalkyl substituted by one or more R R 3-1 is C1-C3 alkyl; R 3-2 is D or halogen; R 4 is methyl or methyl substituted with 1-3 D; Preferably, For wherein n is 0, 1, 2, or 3, each R 1 each independently D, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; k is 0, 1, 2, or 3 (more preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2 each independently D, -OH, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH); (2) I-1-2' (e.g., I-1-2-1' or I-1-2-2') n' is 0, 1, 2, 3, 4, 5, 6, or 7; each R 1 each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; R 2 is D, -OH or halogen; L' is -0-, -(CH2) m - or -(CD2) m -, m is 1 or 2; R 3 C3-C8cycloalkyl substituted by one or more R 3-1 C3-C8cycloalkyl substituted by one or more R 3-2 C3-C8cycloalkyl substituted by one or more R R 3-1 is C1-C3 alkyl; R 3-2 is D or halogen; R 4 is methyl or methyl substituted with 1-3 D; Preferably, For wherein n is 0, 1, 2, or 3, each R 1 each independently D, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; k is 0, 1, 2, or 3 (more preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2 each independently D, -OH, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH); (3) in compounds I-3-1' (e.g., I-3-1-1' or I-3-1-2') and I-4-1' (e.g., I-4-1-1' or I-4-1-2'), n' is 0, 1, 2, 3, 4, 5, 6, or 7; each R 1 each independently D, -OH, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; o is 0 or 2; each R 2-2 each independently halogen, preferably F; L' is -0-, -(CH2) m - or -(CD2) m - and m is 1 or 2; R 3 C3-C8cycloalkyl substituted by one or more R 3-1 C3-C8cycloalkyl substituted by one or more R 3-2 C3-C8cycloalkyl substituted by one or more R R 3-1 is C1-C3 alkyl; R 3-2 is D or halogen; R 4 is methyl or methyl substituted with 1-3 D; Preferably, For wherein n is 0, 1, 2, or 3, each R 1 each independently D, halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; k is 0, 1, 2, or 3 (more preferably, k is 0); t is 0, 1, 2, 3, 4, 5, or 6 (more preferably, t is 0, 1, 2, 4, or 6); each R 1-1 and R 1-2 each independently D, -OH, halogen (e.g., fluorine), -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens (more preferably, R 1-1 is halogen (e.g., fluorine), R 1-2 is D or -OH).

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, The compound is compound I-1-1, I-1-2 (e.g., I-1-2-1 or I-1-2-2), I-3-1 (e.g., I-3-1-1 or I-3-1-2), or I-4-1 (e.g., I-4-1-1 or I-4-1-2): (e.g. ) (e.g. ) (e.g. ) wherein o is 0, 1 or 2, n, R 1 , R 2 , R 2-2 , L and R 3 are as defined in any one of claims 1-8; Preferably, the compound is any one of the following: (1) in compound I-1-1, n is 0 or 1; each R 1 each independently halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; L is -O- or -(CH2) m - and m is 1 or 2; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; (2) compound I-1-2 (e.g. I-1-2-1 or I-1-2-2) wherein n is 0 or 1; each R 1 each independently halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; R 2 is D, -OH or halogen; L is -O- or -(CH2) m - and m is 1 or 2; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; (3) compound I-3-1 (e.g. I-3-1-1 or I-3-1-2) and I-4-1 (e.g. I-4-1-1 or I-4-1-2) wherein n is 0 or 1; each R 1 each independently halogen, -O-Ci-C6alkyl, or Ci-C6alkyl substituted with one or more halogens; o is 0 or 2; each R 2-2 each independently halogen, preferably F; L is -O- or -(CH2) m - and m is 1 or 2; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; More preferably, the compound is according to any one of the following: (1) compound I-1-1 wherein n is 1; R 1 is halogen; preferably F; L is O or -CH2-; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 is C1-C3 alkyl; (2) compound I-1-2 (e.g. I-1-2-1 or I-1-2-2) wherein n is 1; R 1 is halogen; preferably F; R 2 is halogen; preferably F; L is O or -CH2-; R 3 C1-C6-alkyl or C3-C8-cycloalkyl, each of which is optionally substituted by one or more R 3-1 substituted C3-C8-cycloalkyl; R 3-1 is C1-C3 alkyl; (3) compound I-3-1 (e.g. I-3-1-1 or I-3-1-2) and I-4-1 (e.g. I-4-1-1 or I-4-1-2) wherein n is 1; R 1 is halogen; preferably F; o is 0 or 2; each R 2-2 each independently halogen; preferably F; L is -CH2-; R 3 is Ci-C6-alkyl; preferably tert-butyl; Further more preferably, the compound is according to any one of the following: (1) compound I-1-1 wherein n is 1; R 1 is halogen; preferably F; L is -CH2-; R 3 C1-C6alkyl, C3-C8cycloalkyl, or -Si(C1-C6alkyl)3; preferably, R 3-1 C1-C6alkyl, C3-C8cycloalkyl, or -Si(C1-C6alkyl)3; preferably, R 3-1 C1-C3alkyl; preferably, R 3 C1-C3alkyl; preferably, R (2) compound I-1-2 (e.g. I-1-2-1 or I-1-2-2) wherein n is 1; R 1 is halogen; preferably F; R 2 is halogen; preferably F; L is -CH2-; R 3 It is a C1-C6 alkyl group or is composed of one or more R groups. 3-1 Substituted C3-C8 cycloalkyl or -Si(C1-C6 alkyl)3; R 3-1 It is a C1-C3 alkyl group; preferably, R 3 For tert-butyl, (3) compound I-3-1 (e.g. I-3-1-1 or I-3-1-2) and I-4-1 (e.g. I-4-1-1 or I-4-1-2) wherein n is 1; R 1 is halogen; preferably F; o is 0; L is -CH2-; R 3 is C1-C6 alkyl; preferably tert-butyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein, which satisfies one or more of the following conditions: (1) For (2) For (3) For (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example ) or (For example )； (4) For Preferably and (5) For 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein, The compound is any one of the following compounds: (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) (e.g. ) 12. A compound III’, wherein Rings A, L', R 3 and R 4 are as defined in any one of claims 1-11; Preferably, The compound III' is any one of the following structures: (For example )、 (For example ) or (For example )。 13. A process for preparing a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, characterized in that, the preparation method is according to Scheme 1' or Scheme 2': Scheme 1': comprising the step of subjecting compound II' or a salt thereof and compound III' to a coupling reaction as shown below in the presence of a catalyst, preferably a Pd catalyst, and a base in a solvent, preferably toluene, to give compound I'; Scheme 2': comprising the step of subjecting compound IV' and compound V' to the reaction as shown below in the presence of a strong base in a solvent, to give compound I'; wherein n', R 1 ', ring A, L', R 3 and R 4 are as defined in any one of claims 1-11.

14. A pharmaceutical composition, characterized by, the pharmaceutical composition comprises: (1) a compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof or a compound prepared according to the preparation method of claim 13 or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable excipient.

15. Use of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, a compound made by the process of claim 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14. the use is as a KCNQ2 / 3 channel opener or for the preparation of a medicament for preventing or treating 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. 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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