Heteroaryl derivatives and their use

Abstract

The present invention discloses heteroaryl derivatives and their uses, specifically compounds represented by formulas (I) and (V) or pharmaceutically acceptable salts thereof. JPEG2026534522000157.jpg35170

Description

[Technical Field]

[0001] This invention relates to: 1) the priority rights and benefits of Chinese patent application No. 202311284906.6 filed with the China National Intellectual Property Administration on September 28, 2023; 2) the priority rights and benefits of Chinese patent application No. 202311410637.3 filed with the China National Intellectual Property Administration on October 26, 2023; and 3) the priority rights and benefits of Chinese patent application No. 202311849240.4 filed with the China National Intellectual Property Administration on December 28, 2023. This application claims priority and interest, 4) priority and interest to Chinese patent application No. 202410539834.3 filed with the China National Intellectual Property Administration on 29 April 2024, and 5) priority and interest to Chinese patent application No. 202411320022.6 filed with the China National Intellectual Property Administration on 20 September 2024, with the entirety of the contents disclosed in the said application being incorporated herein by reference.

[0002] The present invention relates to heteroaryl derivatives and their use, and more specifically to compounds represented by formulas (I) and (V) or pharmaceutically acceptable salts thereof. [Background technology]

[0003] Voltage-dependent Kv7 / KCNQ potassium ion channels are widely present in the nervous system and play a crucial role in regulating neuronal excitability. Research into Kv7 potassium ion channel openers offers ample room for the development of new drugs to treat hyperexcitability-related disorders such as epilepsy and pain.

[0004] The Kv7 family has five subtypes, of which Kv7.2 and Kv7.3 (encoded by KCNQ2 and KCNQ3) are homologous subunits that form widely expressed neuronal voltage-gated potassium ion channels and are key subunits involved in the regulation of neuronal signaling and the hyperexcitatory state of epilepsy. KCNQ2 and KCNQ3 are mainly distributed in the brain, highly expressed in the cerebellar cortex, amygdala, caudate nucleus, and hippocampus, forming homologous / heterotetramers (M-type potassium ion channels) and the molecular basis for the formation of M-currents. Increased M-currents can hyperpolarize the cell membrane, reduce neuronal excitability, and prevent the generation and propagation of action potential explosions and the resulting seizures. Enhancing the open state of Kv7.2 / Kv7.3 channels in neurons is beneficial for the resting state of hyperpolarization, reducing spikes in fast action potentials (i.e., explosive discharges) and stabilizing the resting membrane potential of neurons, thereby limiting neuronal excitability, which is also a cause of the antiepileptic drug effect.

[0005] Retigavin is a key focus in the clinical treatment of neurological disorders such as epilepsy, as KCNQ2 / 3 potassium channel openers have clinically demonstrated superiority in treating seizures and epilepsy. XEN1101 from biopharmaceutical company Xenon has already entered Phase 3 clinical trials and is being used to treat focal epileptic seizures. Biohaven's BHV-7000 has also completed Phase 1 clinical trials, showing a significant reduction in associated side effects and is a very promising drug for treating neurological conditions such as epilepsy and pain. [Overview of the project]

[0006] The present invention provides compounds represented by formula (I) or (V) or pharmaceutically acceptable salts thereof.

[0007] [ka] (In the formula, Ring A is selected from 9-10 membered bicycloheteraryl groups. Ring B is fused with Ring A, and Ring B is C 4~7 cycloalkyl group, C 4~7 selected from a cycloalkenyl group, a 4 to 7-membered heterocycloalkyl group and a 4 to 7-membered heterocycloalkenyl group, each R1 is independently selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, C 2~4 alkyl group, C 1~4 alkoxy group, C 3~7 selected from a cycloalkyl group and a 4 to 7-membered heterocycloalkyl group, and the aforementioned C 2~4 alkyl group, C 1~4 alkoxy group, C 3~7 cycloalkyl group and 4 to 7-membered heterocycloalkyl group are each independently optionally substituted with 1, 2 or 3 R a , R2 is selected from a cyclobutyl group, C 5~8 bridged ring cycloalkyl group, C 5~8 spiro ring cycloalkyl group, phenyl group, 5 to 6-membered heteroaryl group, 4 to 7-membered heterocycloalkyl group and C 5~8 selected from a cycloalkenyl group, and the aforementioned cyclobutyl group, C 5~8 bridged ring cycloalkyl group, C 5~8 spiro ring cycloalkyl group, phenyl group, 5 to 6-membered heteroaryl group, 4 to 7-membered heterocycloalkyl group and C 5~8 cycloalkenyl group are each independently optionally substituted with 1, 2 or 3 R b , R3 is selected from H and -C(O)C 1~4 alkyl group, R4 is C 1~6 alkyl group, C 1~6 alkoxy group, -CH2-C 3~7 selected from a cycloalkyl group and -CH2-4 to 7-membered heterocycloalkyl group, and the aforementioned C 1~6 alkyl group, C 1~6 alkoxy group, -CH2-C 3~7 cycloalkyl group and -CH2-4 to 7-membered heterocycloalkyl group are each independently optionally substituted with 1, 2, 3, 4 or 5 R c , Each R5 is independently H, F, Cl, Br, I, =O, C 1~4 Alkyl and C 1~4 Selected from alkoxy groups, the C 1~4 Alkyl and C 1~4 Each alkoxy group can be independently substituted with one, two, or three halogens. Each R6 is independently H, F, Cl, Br, I, CN, C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7 Selected from cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, and phenyl groups, the C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7 Cycloalkyl groups, 4- to 7-membered heterocycloalkyl groups, and phenyl groups can each independently optionally have 1, 2, or 3 R groups. 6a Replaced by each R a and R c Each of these is independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, and CF3. Each R b These are H, F, Cl, Br, I, =O, OH, NH2, CN, and C, respectively, independently. 1~4 Alkyl and C 1~4 Selected from alkoxy groups, the C 1~4 Alkyl and C 1~3 Each alkoxy group can be independently substituted with any 1, 2, or 3 F atoms. Each R 6a These are H, F, Cl, Br, I, OH, NH2, CN, and C, respectively, independently. 1~4 Alkyl and C 1~4 Selected from alkoxy groups, the C 1~4 Alkyl and C 1~4 Each alkoxy group can be independently substituted with any 1, 2, 3, 4, or 5 fluorine atoms. m is selected from 1, 2, 3, and 4. p and q are independently selected from 1, 2, and 3, respectively. As a condition, 1) R2 is selected from a phenyl group and a 5-6 membered heteroaryl group, and the phenyl group and the 5-6 membered heteroaryl group can each be independently of any 1, 2, or 3 R b If replaced by, structural fragment [ka] teeth, [ka] Selected from, or, 2) R2 is selected from cyclobutyl groups, and the cyclobutyl groups are arbitrarily 1, 2, or 3 R b When replaced, m is selected from 2, 3, and 4. In some technical means of the present invention, each of the above R a Each of these is independently selected from H, F, and OH, and the other variables are as defined in this invention.

[0008] In some technical means of the present invention, each of the above R b Each of these is independently selected from H, F, =O, CH3, and OCF3, and the other variables are as defined in this invention.

[0009] In some technical means of the present invention, each of the above R c These are independently selected from H, F, and CH3, and the other variables are as defined in this invention.

[0010] In some technical means of the present invention, each of the above R1 is independently selected from H, F, Cl, OH, NH2, CN, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group, and each of the above CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group is independently selected from 1, 2 or 3 R a It is replaced by and the other variables are as defined in this invention.

[0011] In some technical means of the present invention, each of the above R1 is independently H, F, CN, CF3 and [ka] Selected from the above, the other variables are as defined in this invention.

[0012] In some technical means of the present invention, R2 is C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Selected from spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups, the C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups each independently optionally have 1, 2, or 3 R groups. b It is replaced by and the other variables are as defined in this invention.

[0013] In some technical means of the present invention, R2 is selected from a cyclobutyl group, a spiro[3.3]heptanyl group, a bicyclo[1.1.1]pentyl group, a phenyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, an oxetanyl group, an azacyclobutyl group, a piperidinyl group, a piperazinyl group, a cyclopentenyl group, and a cyclohexenyl group, and each of the cyclobutyl group, spiro[3.3]heptanyl group, a bicyclo[1.1.1]pentyl group, a phenyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, an oxetanyl group, an azacyclobutyl group, a piperidinyl group, a piperazinyl group, a cyclopentenyl group, and a cyclohexenyl group can be any one, two, or three R groups independently. b It is replaced by and the other variables are as defined in this invention.

[0014] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0015] In some technical means of the present invention, R2 is [ka] The other variables are as defined in this invention.

[0016] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0017] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0018] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0019] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0020] In some technical means of the present invention, R4 is CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, [ka] Selected from the above, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, [ka] Each of these can be any 1, 2, 3, 4, or 5 Rs, independently of each other. c It is replaced by and the other variables are as defined in this invention.

[0021] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0022] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0023] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0024] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0025] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0026] In some technical means of the present invention, the above structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0027] In some technical means of the present invention, the above structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0028] In some technical means of the present invention, the above structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0029] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0030] [ka] (In the formula, Each R1 independently contains H, F, Cl, Br, I, OH, NH2, CN, CF3, and C. 2~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7 Selected from cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups, the C 2~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7 Cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups each independently optionally have 1, 2, or 3 R groups. a Replaced by, R2 is a cyclobutyl group, C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups, 4-7 membered heterocycloalkyl groups, and C 5~8 Selected from cycloalkenyl groups, the cyclobutyl group, C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups, 4-7 membered heterocycloalkyl groups, and C 5~8 Each cycloalkenyl group can independently have any 1, 2, or 3 R groups. b Replaced by, R3 is H and -C(O)C 1~4 Selected from alkyl groups, R4 is C 1~6 alkyl group, C 1~6 alkoxy group, -CH2-C 3~7 cycloalkyl group, -CH2-4~7 membered heterocycloalkyl group, and said C 1~6 alkyl group, C 1~6 alkoxy group, -CH2-C 3~7 cycloalkyl group, and -CH2-4~7 membered heterocycloalkyl group are each independently optionally substituted with 1, 2, 3, 4 or 5 R c each R a and R c are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 and CF3, each R b is each independently selected from H, F, Cl, Br, I, =O, OH, NH2, CN, C 1~4 alkyl group and C 1~4 alkoxy group, and said C 1~4 alkyl group and C 1~3 alkoxy group are each independently optionally substituted with 1, 2 or 3 F, m is selected from 1, 2, 3, 4, as a condition, 1) when R2 is selected from a phenyl group and a 5~6 membered heteroaryl group, and said phenyl group and 5~6 membered heteroaryl group are each independently optionally substituted with 1, 2 or 3 R b , the structural fragment [Chemical Formula] is [Chemical Formula] , or 2) when R2 is selected from a cyclobutyl group, and said cyclobutyl group is optionally substituted with 1, 2 or 3 R b , m is selected from 2, 3 and 4.) The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. ​

[0031]

Chemical formula

[0032] [ka] (In the formula, Each R1 is independently F, Cl, Br, I, OH, NH2, CN, C 2~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7 Selected from cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups, the C 2~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7Cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups each independently optionally have 1, 2, or 3 R groups. a Replaced by, R2 is a cyclobutyl group, C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Selected from a spirocyclic cycloalkyl group, a phenyl group, a 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group, the cyclobutyl group, C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups, and 4-7 membered heterocycloalkyl groups can each independently optionally have 1, 2, or 3 R groups. b Replaced by, R3 is H and -C(O)C 1~4 Selected from alkyl groups, R4 is C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, -CH2-C 3~7 Selected from cycloalkyl groups and heterocycloalkyl groups of -CH2-4 to 7 members, the C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, -CH2-C 3~7 Each cycloalkyl group and -CH2-4 to 7-membered heterocycloalkyl group can independently have 1, 2, 3, 4, or 5 R groups. c Replaced by, Each R a and R c Each of these is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, and CF3. Each R b These are F, Cl, Br, I, OH, NH2, CN, and C, respectively, independently. 1~4 Alkyl and C 1~4 Selected from alkoxy groups, the C 1~4 Alkyl and C 1~3 Each alkoxy group can be independently substituted with any 1, 2, or 3 F atoms. m is selected from 1, 2, 3, and 4. As a condition, 1) R2 is selected from a phenyl group and a 5-6 membered heteroaryl group, and the phenyl group and the 5-6 membered heteroaryl group can each be independently of any 1, 2, or 3 R b If replaced by, structural fragment [ka] teeth, [ka] Selected from, or, 2) R2 is selected from cyclobutyl groups, and the cyclobutyl groups are arbitrarily 1, 2, or 3 R b When replaced, m is selected from 2, 3, and 4. In some technical means of the present invention, each of the above R a Each of these is independently selected from H, F, and OH, and the other variables are as defined in this invention.

[0033] In some technical means of the present invention, each of the above R a These are independently selected from F and OH, and the other variables are as defined in this invention.

[0034] In some technical means of the present invention, each of the above R b Each of these is independently selected from H, F, =O, CH3, and OCF3, and the other variables are as defined in this invention.

[0035] In some technical means of the present invention, each of the above R b These are independently selected from F, CH3, and OCF3, and the other variables are as defined in this invention.

[0036] In some technical means of the present invention, each of the above R c These are independently selected from H, F, and CH3, and the other variables are as defined in this invention.

[0037] In some technical means of the present invention, each of the above R cThese are independently selected from F and CH3, and the other variables are as defined in this invention.

[0038] In some technical means of the present invention, each of the above R1 is independently selected from H, F, Cl, OH, NH2, CN, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group, and each of the above CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group is independently selected from 1, 2 or 3 R a It is replaced by and the other variables are as defined in this invention.

[0039] In some technical means of the present invention, each of the above R1 is independently H, F, CN, CF3 and [ka] Selected from the above, the other variables are as defined in this invention.

[0040] In some technical means of the present invention, each of the above R1 is independently selected from H, F, CN, and CF3, and the other variables are as defined in the present invention.

[0041] In some technical means of the present invention, each of the above R1 is independently selected from H, F, Cl, OH, NH2, CN, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group, and each of the above CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group is independently selected from 1, 2 or 3 R a It is replaced by and the other variables are as defined in this invention.

[0042] In some technical means of the present invention, each of the above R1 is H, F, CN and [ka] Selected from the above, the other variables are as defined in this invention.

[0043] In some technical means of the present invention, each of the above R1 is independently selected from F, Cl, OH, NH2, CN, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group, and each of the above CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group is independently selected from 1, 2 or 3 R a It is replaced by and the other variables are as defined in this invention.

[0044] In some technical means of the present invention, each of the above R1 is F, CN and [ka] Selected from the above, the other variables are as defined in this invention.

[0045] In some technical means of the present invention, R2 is C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups, 4- to 7-membered heterocycloalkyl groups, and C 5~8 Selected from the cycloalkenyl groups, the C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups, 4- to 7-membered heterocycloalkyl groups, and C 5~8 Each cycloalkenyl group can independently have any 1, 2, or 3 R groups. b It is replaced by and the other variables are as defined in this invention.

[0046] In some technical means of the present invention, R2 is C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Selected from spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups, the C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups each independently optionally have 1, 2, or 3 R groups. b It is replaced by and the other variables are as defined in this invention.

[0047] In some technical means of the present invention, in some technical means of the present invention, the above R2 is C 5~8 Crosslinked ring cycloalkyl groups and C 5~8 Selected from cycloalkenyl groups, the C 5~8 Crosslinked cycloalkyl groups and C 5~8 Each cycloalkenyl group can independently have any 1, 2, or 3 R groups. b It is replaced by and the other variables are as defined in this invention.

[0048] In some technical means of the present invention, in some technical means of the present invention, the above R2 is C 5~8Selected from crosslinked ring cycloalkyl groups, the C 5~8 The crosslinked ring cycloalkyl group may optionally have 1, 2, or 3 R b It is replaced by and the other variables are as defined in this invention.

[0049] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0050] In some technical means of the present invention, R2 is selected from a cyclobutyl group, a spiro[3.3]heptanyl group, a bicyclo[1.1.1]pentyl group, a phenyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, an oxetanyl group, an azacyclobutyl group, a piperidinyl group, a piperazinyl group, a cyclopentenyl group, and a cyclohexenyl group, and each of the cyclobutyl group, spiro[3.3]heptanyl group, a bicyclo[1.1.1]pentyl group, a phenyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, an oxetanyl group, an azacyclobutyl group, a piperidinyl group, a piperazinyl group, a cyclopentenyl group, and a cyclohexenyl group can be any one, two, or three R groups independently. b It is replaced by and the other variables are as defined in this invention.

[0051] In some technical means of the present invention, R2 is selected from a cyclobutyl group, a spiro[3.3]heptanyl group, a bicyclo[1.1.1]pentyl group, a phenyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, an oxetanyl group, an azacyclobutyl group, a piperidinyl group, and a piperazinyl group, and each of the cyclobutyl group, spiro[3.3]heptyl group, a bicyclo[1.1.1]pentyl group, a phenyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, an oxetanyl group, an azacyclobutyl group, a piperidinyl group, and a piperazinyl group can be any one, two, or three R groups independently. b It is replaced by and the other variables are as defined in this invention.

[0052] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0053] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0054] In some technical means of the present invention, R2 is C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Selected from spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups, the C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups each independently optionally have 1, 2, or 3 R groups. b It is replaced by and the other variables are as defined in this invention.

[0055] In some technical means of the present invention, R2 is [ka] Selected from the above, the other variables are as defined in this invention.

[0056] In some technical means of the present invention, R4 is CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, [ka] Selected from the above, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, [ka] Each of these can be any 1, 2, 3, 4, or 5 Rs, independently of each other. c It is replaced by and the other variables are as defined in this invention.

[0057] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0058] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0059] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0060] In some technical means of the present invention, R4 is [ka] Selected from the above, the other variables are as defined in this invention.

[0061] In some technical means of the present invention, R4 is [ka] are selected from, and other variables are as defined in the present invention. In some technical solutions of the present invention, the above structural unit

化

化

[0062] In some technical solutions of the present invention, the above structural unit

化

化

[0063] In some technical solutions of the present invention, the above structural unit

化

化

[0064] In some technical solutions of the present invention, the above structural unit

化

化

[0065] In some technical solutions of the present invention, the above compound or a pharmaceutically acceptable salt thereof is

Chemical formula

Chemical formula

Chemical formula

[0066] In some technical solutions of the present invention, the above compound or a pharmaceutically acceptable salt thereof is

Chemical formula

[0067] In some technical solutions of the present invention, the above compound or a pharmaceutically acceptable salt thereof is ​​ [ka] Selected from, During the ceremony, R2 is C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Selected from spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups, the C 5~8 Crosslinked ring cycloalkyl group, C 5~8 Spirocyclic cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups each independently optionally have 1, 2, or 3 R groups. b Replaced by, Each R1, R4, R b And m are as defined in the present invention.

[0068] In some technical means of the present invention, the above compound or a pharmaceutically acceptable salt thereof is [ka] Selected from, In the formula, R2 and R4 are as defined in the present invention.

[0069] The present invention further provides a compound represented by formula (I') or a pharmaceutically acceptable salt thereof.

[0070] [ka] (In the formula, Ring A is selected from 9-10 membered bicycloheteraryl groups. Ring B is fused with ring A, and ring B is C 4~7 Cycloalkyl groups, C 4~7 Selected from cycloalkenyl groups, 4-7 membered heterocycloalkyl groups, and 4-7 membered heterocycloalkenyl groups, Each R5 is independently H, F, Cl, Br, I, =O, C 1~4 Alkyl and C 1~4 Selected from alkoxy groups, the C 1~4 Alkyl and C 1~4Each alkoxy group can be independently substituted with one, two, or three halogens. Each R6 is independently H, F, Cl, Br, I, CN, C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7 Selected from cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, and phenyl groups, the C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group, C 3~7 Cycloalkyl groups, 4- to 7-membered heterocycloalkyl groups, and phenyl groups can each independently optionally have 1, 2, or 3 R groups. 6a It is replaced with, and R4 is C 1~6 Alkyl, -CH2-C 3~7 Selected from cycloalkyl groups, -CH2-4 to 7-membered heterocycloalkyl groups, and -CH2-phenyl groups, the C 1~6 Alkyl, -CH2-C 3~7 Cycloalkyl groups, -CH2-4 to 7-membered heterocycloalkyl groups, and -CH2-phenyl groups can each independently have 1, 2, 3, 4, or 5 R groups. c Replaced by, Each R 6a These are H, F, Cl, Br, I, OH, NH2, CN, and C, respectively, independently. 1~4 Alkyl and C 1~4 Selected from alkoxy groups, the C 1~4 Alkyl and C 1~4 Each alkoxy group can be independently substituted with any 1, 2, 3, 4, or 5 fluorine atoms. Each R c Each of these is independently selected from H, F, Cl, Br, I, CH3, and CF3. m and n are independently selected from 1, 2, and 3. In some technical means of the present invention, each of the above R5 is independently selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0071] In some technical means of the present invention, each of the above R6 is independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, azacyclobutyl group and phenyl group, and each of the above CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, azacyclobutyl group and phenyl group is independently selected from 1, 2 or 3 R 6a It is replaced by and the other variables are as defined in this invention.

[0072] In some technical means of the present invention, each of the above R6 is independently H, F, Cl, CH3, CF3, CH2CH3, C(CH3)3, CN and [ka] Selected from the above, the other variables are as defined in this invention.

[0073] In some technical means of the present invention, each of the above R6 is independently selected from H, F, Cl, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group, and each of the above CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group is independently selected from 1, 2 or 3 R 6a It is replaced by and the other variables are as defined in this invention.

[0074] In some technical means of the present invention, each of the above R6 is independently H, F, Cl, CH3, CF3, CH2CH3, C(CH3)3, CN and [ka] Selected from the above, the other variables are as defined in this invention.

[0075] In some technical means of the present invention, R4 is CH2C(CH3)3, [ka] Selected from, the CH2C(CH3)3, [ka] Each of these can be any 1, 2, 3, 4, or 5 Rs, independently of each other. c It is replaced by and the other variables are as defined in this invention.

[0076] In some technical means of the present invention, R4 is CH2C(CH3)3, [ka] Selected from the above, the other variables are as defined in this invention.

[0077] In some technical means of the present invention, ring A is selected from a benzimidazolyl group, a benzopyrazolyl group, a pyridoimidazolyl group, a pyridopyrazolyl group, a pyrimidoimidazolyl group, a pyrimidopyrazolyl group, an indolyl group, and a pyridadoimidazolyl group, with the other variables being as defined in the present invention.

[0078] In some technical means of the present invention, ring A is selected from a benzimidazolyl group, a benzopyrazolyl group, a pyridoimidazolyl group, a pyridopyrazolyl group, a pyrimidoimidazolyl group, and a pyrimidopyrazolyl group, and the other variables are as defined in the present invention.

[0079] In some technical means of the present invention, ring B is selected from a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, a cyclohexenyl group, a tetrahydropyrrolyl group, a dihydropyrrolyl group, a tetrahydrofuranyl group, a dihydrofuranyl group, a tetrahydrothiophenyl group, a dihydrothiophenyl group, a 1,3-dioxolyl group, and a 1,4-dioxolyl group, the other variables being as defined in the present invention.

[0080] In some technical means of the present invention, ring B is selected from a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, a cyclohexenyl group, a pyrrolidinyl group, and a pyrrolyl group, and the other variables are as defined in the present invention.

[0081] In some technical means of the present invention, the above structural unit [ka] teeth, [ka] Selected from, in the formula, R 5、 R6 and p are as defined in the present invention.

[0082] Some further aspects of the present invention involve any combination of the above variables.

[0083] The present invention [ka] [ka] [ka] The present invention further provides a compound represented by the formula shown, or a pharmaceutically acceptable salt thereof.

[0084] The present invention further provides a pharmaceutical composition comprising a therapeutic or prophylactic effective amount of the compound described in the present invention, its stereoisomer, and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.

[0085] The present invention further provides the use of the above compound or a pharmaceutically acceptable salt thereof in the manufacture of drugs for treating Kv7 potassium ion channel opener-related diseases.

[0086] In some aspects of the present invention, the Kv7 potassium ion channel opener-related disorders include, but are not limited to, epilepsy, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorders, stroke, Alzheimer's disease, neurodegenerative diseases, neuronal hyperexcitability, complications of cocaine abuse, nicotine withdrawal syndrome, alcohol withdrawal syndrome, and tinnitus.

[0087] In some aspects of the present invention, the Kv7 potassium ion channel includes Kv7.2, Kv7.3, Kv7.4, and Kv7.5, and is preferably Kv7.2 and Kv7.3.

[0088] The present invention further provides the following synthesis routes 1 to 7.

[0089] Route 1, [ka] Route 2, [ka] Route 3, [ka] Route 4, [ka] Route 5, [ka] Route 6, [ka] Route 7, [ka] The present invention further provides the following test methods 1 and 2.

[0090] Test Method 1: Thallium flow analysis test using hKCNQ2 / 3 Experimental Objective: In a stable hKCNQ2 / 3 CHO cell line, the in vitro concentration-response relationship of compounds was investigated using FLIPR thallium flux.

[0091] Regarding experimental cells and reagents, (1)Cell line: hKCNQ2 / 3 CHO cells were stably transfected.

[0092] (2) Cell medium reagents: Cell culture reagent information is shown in Table 1.

[0093] Table 1: Cell culture reagent information [Table 1]

[0094] (3)Cell culture: The cell line was passaged three times weekly at a passage ratio of 1:2 to 1:3. When the cells proliferated to confluence >80% in the T-75 cell bottle, they were digested with 0.25% trypsin-EDTA solution for approximately 1 minute, transferred from the cell bottle, and passaged. Depending on the passage ratio, the cells were transferred to another T-75 cell bottle containing complete cell growth medium. Note: To maintain logarithmic cell proliferation, it was necessary to maintain cell proliferation in a subconfluent monolayer state. Cells were passaged every 2-3 days, depending on the time it took for the cells to double.

[0095] Experimental flow: (1) Day 1, cell preparation: Cells were digested using the method described above, and cell density and vitality were measured using Cell Countess. The volume of the single-cell suspension was adjusted with complete cell growth medium. Next, hKCNQ2 / 3_CHO cells were inoculated into 384-well plates pre-coated with PDL at a density of approximately 20,000 cells / well (30 μL / well). The plates were then incubated overnight in an incubator at 37°C with 5% CO2 humid air.

[0096] (2) The following day, preparation of the compounds: The compounds to be measured were diluted to storage concentration with dimethyl sulfoxide (DMSO) and stored in a refrigerator at -20°C. The compound addition program was set on the ECHO liquid workstation, and the compounds were added to plates using ECHO. Retigabine (RTG) was used as a positive reference, with a maximum concentration of 100 μM, diluted 3-fold, and nine doses were prepared as plate layouts required for plating. 5 mM K + and 1mM Tl + Plates were prepared using a stimulating buffer containing [the specified substance].

[0097] Note: 1) K2SO4 and Tl2SO4 were prepared in 1× chloride-free buffer. If the voltage-dependent potassium channels are different, Tl + and K + The concentration needed to be adjusted. + The concentration is approximately 0.5 mM to 5 mM, K + The concentration was set to approximately 5 mM to 30 mM. 2) K2SO4 and Tl2SO4 were prepared with 2 mM K per 1 mM solution. + and Tl + It contained [unclear], and the final concentration had to be calculated from the ion concentration. 3) TlCl precipitates easily, so a chloride-free buffer solution had to be used.

[0098] (3) The next day, experimental test: After the cells reached confluence, the cell analysis plate was removed from the incubator. Prepare the experimental buffer, Tl + The dye was diluted (molecular instrument #R8222). The culture medium was discarded using the Bravo liquid workstation, and 25 μL of Tl was added to each well. +Dye was added. After incubation for 1 hour, the cell analysis plate, composite plate, and FLIPR tip were placed in FLIPRTETRA (Molecular Devices, USA) and FLIPR detection was performed. After setting the needle tip, the baseline was read at 60 seconds, then 12.5 μL was added from the composite plate (3×) to the cell analysis plate, and data was recorded simultaneously for at least 5 minutes.

[0099] (4) Data Processing: The maximum signal was generated using FLIPR software. Excel (2013) and Prism 6.01 were used for data analysis. Data quality was controlled to S / B > 2.00 and Z coefficient > 0.50. IC 50 or EC 50 This was defined as the median line between the lowest-ranking and highest-ranking platforms, and was calculated using Prism 6.01 and a 4-parameter logistic model.

[0100] Test Method 2: Pharmacokinetic Evaluation in Mice Experimental Method: The test compound was mixed with 5% DMSO / 60% polyethylene glycol (PEG400) / 35% water, vortexed, and sonicated to prepare a 0.2 mg / mL clear solution, which was filtered through a microfiltration membrane for use. 25g-35g male CD-1 mice were selected and administered the candidate compound solution intravenously at a dose of 1 mg / kg. After fasting, the candidate compound solution was administered orally at a dose of 5 mg / kg. After animal administration, 25 μL of blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours, and placed in commercial anticoagulation tubes pre-added with EDTA-K2. The test tubes were centrifuged for 10 minutes to separate the plasma, which was then stored at -60°C. The target compound content in the plasma samples was measured by LC / MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA).

[0101] Regarding the definition of each parameter, IV: intravenous injection, PO: oral, C0: instantaneous required concentration after intravenous injection, C max : The highest level of drug concentration in the blood after administration, T max: The time required to reach the drug's peak concentration after administration, T 1 / 2 :Time required for the drug blood concentration to decrease by half, Vdss:Apparent distribution volume, which is the ratio constant between the in vivo drug amount and the drug blood concentration when the drug reaches dynamic balance in vivo. Cl:Clearance, which is the number of apparent distribution volumes of the drug removed from in vivo per unit time, T last : Refers to the time of the last detection point, AUC 0-last : This is the area under the drug-time curve, referring to the area enclosed by the drug blood concentration curve over time. F: This is one measure of the speed and extent to which a drug is absorbed and enters the bloodstream, and is an important indicator for evaluating the degree of drug absorption.

[0102] Technical effects The compounds of the present invention bind well to the Kv7.2 protein and the human-derived Kv7.3 protein, which has a highly homologous binding site, exhibit a significant agonist effect on the hKCNQ2 / 3 potassium ion channel, possess excellent pharmacokinetic properties, and can exert excellent pharmacological effects.

[0103] Definition and Description Unless otherwise stated, the following terms and phrases used herein are intended to have the meanings set forth below. No particular term or phrase should be considered uncertain or ambiguous unless specifically defined, and should be understood in a general sense. Where a trade name is mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0104] As used herein, the term “pharmaceutically acceptable” is defined as a compound, material, composition and / or dosage form that, within the bounds of reliable medical judgment, is suitable for contact with human and animal tissues, has little toxicity, irritation, allergic reaction or other problem or complication, and is commensurate with a reasonable benefit / risk ratio.

[0105] The term "pharmaceutically acceptable salt" refers to a salt of the compound according to the present invention, and means a salt prepared with a relatively non-toxic acid or base of a compound having a specific substituent discovered in the present invention. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting these compounds with a sufficient amount of base in a single solution or a suitable inert solvent. When the compound of the present invention contains a relatively alkaline functional group, an acid addition salt can be obtained by contacting these compounds with a sufficient amount of acid in a single solution or a suitable inert solvent. Some specific compounds of the present invention contain alkaline and acidic functional groups and can therefore be converted into any base addition salt or acid addition salt.

[0106] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid group or a base by conventional chemical methods. Typically, such salts are produced by reacting these compounds in the form of a free acid or base with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof.

[0107] "Pharmaceutical composition" means a composition comprising one or more compounds described herein, their isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and contribute to the absorption of the active ingredient in order to exert biological activity.

[0108] The term "pharmaceutically acceptable adjuvant" refers to an adjuvant that does not have any apparent irritant effect on living organisms and does not impair the biological activity and properties of the active compound. Suitable adjuvant are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water.

[0109] The pharmaceutical compositions of the present invention can be prepared by combining the compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable adjuvant.

[0110] The pharmaceutical composition of the present invention can be manufactured by conventional methods well known in the art, such as mixing, dissolution, granulation, sugar-coated pill manufacturing, grinding, emulsification, and freeze-drying.

[0111] The term "treatment" means administering a compound or preparation described in the present invention to improve or eliminate a disease or one or more symptoms related to the above disease. (i) To suppress the disease or the state of the disease, that is, to suppress its progression, (ii) including alleviating a disease or disease state, that is, eliminating the disease or disease state.

[0112] The term "prevention" means preventing a disease or one or more symptoms associated with the disease by administering a compound or formulation described in the present invention, preventing the manifestation of the disease or disease state in a mammal, in particular including a mammal that is susceptible to the disease state but has not been diagnosed with the disease state.

[0113] The term "therapeutic dose" refers to the dose of the compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The "therapeutic dose" of the compound of the present invention varies depending on the compound, the state and severity of the disease, the method of administration, and the age of the treated mammal, but can be routinely determined by a person skilled in the art based on their knowledge and the content of the present invention.

[0114] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention envisions all compounds such as cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, other mixtures, such as enantiomer- or diastereomer-rich mixtures, all of which fall within the scope of the present invention. Substituents such as alkyl groups may have additional chiral carbon atoms. All of these isomers and mixtures thereof are included within the scope of the present invention.

[0115] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0116] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" refer to those resulting from the inability of a double bond or a single bond on a ring-forming carbon atom to rotate freely.

[0117] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are in a non-mirror image relationship.

[0118] Unless otherwise specified, "(+)" indicates dextrorotatory properties, "(-)" indicates levorotatory properties, and "(±)" indicates a racemic mixture.

[0119] Unless otherwise explained, wedge-shaped solid line connections [ka] and wedge-shaped dashed line connections [ka] This represents the absolute arrangement of a single solid center, and is connected by a straight solid line. [ka] and straight dashed line connections [ka] The wavy line represents the relative arrangement of the center of a solid. [ka] wedge-shaped solid line connection [ka] or wedge-shaped dashed line connection [ka] Represented by or with a wavy line [ka] Straight solid line connection [ka] Or a straight dashed line connection [ka] It represents.

[0120] Unless otherwise specified, the terms “rich in one isomer,” “rich in isomers,” “rich in one enantiomer,” or “rich in enantiomers” mean that the content of one isomer or enantiomer is less than 100%, and that the content of said isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0121] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference in relative percentages between two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the excess (ee value) of the isomer or enantiomer is 80%.

[0122] Optically active (R)- and (S)- isomers and D- and L isomers can be produced by chiral synthesis, chiral reagents, or other conventional techniques. To obtain one enantiomer of a compound of the present invention, it can be produced by asymmetric synthesis or induction using chiral auxiliaries. The resulting diastereomer mixture is then separated, and the auxiliary groups are decomposed to provide the desired pure enantiomer. Alternatively, if the molecule contains an alkaline functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and then the diastereomer is divided and recovered by conventional methods known in the art to obtain the pure enantiomer. Furthermore, the separation of enantiomers and diastereomers is usually performed by chromatography, using a chiral stationary phase and optionally in combination with chemical induction methods (e.g., generating a carbamate salt with an amine).

[0123] Some compounds of the present invention can exist as atropisomers, which are conformational isomers, when rotation around a single bond in the molecule is inhibited or significantly reduced by spatial interactions with other parts of the molecule. The compounds disclosed in the present invention include all atropisomers, which may be pure single atropisomers, those rich in one atropisomer, or nonspecific mixtures thereof. Separation of isomers can be permitted if the rotational potential energy around the single bond is sufficiently high and conformational interconversion is sufficiently slow.

[0124] The compounds of the present invention may contain one or more atoms constituting the compound that are atomic isotopes in non-natural proportions. For example, tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14Compounds can be labeled with radioactive isotopes such as C). Furthermore, for example, hydrogen can be substituted with deuterium to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity and side effects, increased drug stability, enhanced therapeutic effects, and extended biological half-life. All transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0125] The term "substituted" means that one or more hydrogen atoms in a particular atom are replaced by a substituent, and the substituent may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxy group (i.e., =O), it means that two hydrogen atoms are substituted. The term "optionally substituted" means that the substituent may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary as long as they can be realized in a chemically stable manner.

[0126] Any variable (e.g., R) that appears once or more in the composition or structure of a compound is defined independently in each case. Therefore, for example, if a group is substituted with 0 to 2 Rs, the group may be optionally substituted with at most 2 Rs, and in each case, R is independently selected. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0127] When the number of linking groups is 0, for example, -(CRR)0- means that the linking group is a single bond.

[0128] If the number of substituents is 0, it indicates that the substituent is absent; for example, -A-(R)0 indicates that the structure is actually -A.

[0129] If one substituent is empty, it indicates that the substituent is not present. For example, if X in AX is empty, it indicates that the structure is actually A.

[0130] If one of the variables is selected from a single bond, it means that the two groups it connects to are directly linked; for example, if L in ALZ represents a single bond, it means that the structure is actually AZ.

[0131] If the direction of connection is not specified for a given linking group, the direction of connection is arbitrary, for example, [ka] The linking group L in this case is -MW-, and in this case -MW- links ring A and ring B in the same direction as the reading order from left to right. [ka] It is also possible to construct a ring A and ring B by connecting them in the reverse direction of the reading order from left to right. [ka] It may be configured as follows:

[0132] The aforementioned combinations of linking groups, substituents, and / or variants thereof are permissible only if such combinations result in stable compounds.

[0133] Unless otherwise specified, if a group has one or more connectable sites, any one or more sites of the group may be connected to other groups via chemical bonds. If the method of connection of the chemical bonds is undefined and hydrogen atoms are present at the connectable sites, when chemical bonds are connected, the number of hydrogen atoms at the sites decreases in proportion to the number of chemical bonds connected, resulting in a group with the corresponding valency. The chemical bonds that connect the sites to other groups are straight solid bonds. [ka] , straight dashed line connection [ka] or wavy line [ka] It can be represented as follows. For example, a straight solid bond in -OCH3 represents a link to another group via the oxygen atom in that group. [ka] In this case, a straight dashed bond indicates that the nitrogen atom in the group is connected to another group via both ends. [ka] The wavy line in the diagram indicates that the phenyl group is linked to other groups via the carbon atoms at positions 1 and 2. [ka] This indicates that any linkable site in the piperidinyl group can be linked to another group via one chemical bond, at least [ka] This includes four types of linkage methods, and even if an H atom is depicted in -N-, [ka] is still [ka] When a group with a linkage configuration like this is linked, and one chemical bond is linked, the number of H atoms at that site decreases by one, resulting in the corresponding monovalent piperidinyl group.

[0134] Unless otherwise specified, the number of atoms in a ring is usually defined as the number of members in the ring. For example, a "5- to 7-membered ring" refers to a "ring" in which 5 to 7 atoms are arranged in a ring.

[0135] Unless otherwise specified, the term "halo" or "halogen" refers to an atom of fluorine, chlorine, bromine, or iodine, either by itself or as part of another substituent.

[0136] Unless otherwise specified, the term "C" 1~6 The term "alkyl group," either by itself or in combination with other terms, represents a linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1~6 Alkyl groups are C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 2~3 , C 2~4 It may include C3, C4, C5, C6 alkyl groups, and may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). 1~6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl groups), and butyl (including n-butyl, isobutyl, s-butyl, and t-butyl groups).

[0137] Unless otherwise specified, the term "C" 1~4 "Alkyl group" refers to a saturated hydrocarbon group consisting of 1 to 4 carbon atoms, either linear or branched. 1~4 Alkyl groups are C 1~2 , C 1~3 and C 2~3 It may contain alkyl groups, and may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). C 1~4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl groups), and butyl (including n-butyl, isobutyl, s-butyl, and t-butyl groups).

[0138] Unless otherwise specified, the term "C" 2~4The term "alkyl group," either by itself or in combination with other terms, represents a saturated hydrocarbon group consisting of 2 to 4 carbon atoms, either linear or branched. 2~4 Alkyl groups are C 2~4 and C 2~3 It may contain alkyl groups, and may be monovalent (e.g., ethyl group), divalent (e.g., ethylene group), or polyvalent (e.g., ethylene group). C 2~4 Examples of alkyl groups include, but are not limited to, ethyl groups (Et), propyl groups (including n-propyl and isopropyl groups), and butyl groups (including n-butyl, isobutyl, s-butyl, and t-butyl groups).

[0139] Unless otherwise specified, the term "C" 1~4 The term "alkoxy group" refers, either by itself or in combination with other terms, to an alkyl group containing 1 to 4 carbon atoms that is linked to the rest of the molecule via one oxygen atom. 1~4 The alkoxy group is C 1~3 , C 1~2 , C 2~4 , including C4 and C3 alkoxy groups. May be monovalent, divalent, or polyvalent. 1~4 Examples of alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups (including n-propoxy and isopropoxy groups), and butoxy groups (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy groups).

[0140] Unless otherwise specified, the term "C" 1~6 An "alkoxy group" represents an alkyl group containing 1 to 6 carbon atoms that is linked to the rest of the molecule via one oxygen atom. 1~6 The alkoxy group is C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~4 , including C6, C5, C4 and C3 alkoxy groups. 1~6Examples of alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups (including n-propoxy and isopropoxy groups), butoxy groups (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy groups), pentyloxy groups (including n-pentyloxy, isopentyloxy, and neopentyloxy groups), and hexyloxy groups.

[0141] Unless otherwise specified, "C 3~7 "Cycloalkyl group" refers, either by itself or in combination with other terms, to a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms. 3~7 Cycloalkyl groups include monocyclic or polycyclic groups, and polycyclic groups include spirocyclic rings, fused rings, and crosslinking rings. 3~7 Cycloalkyl groups are C 3~5 , C 3~6 , C 4~5 , C 4~6 , C 5~7 It may contain C4, C5, C6, C7 cycloalkyl groups, and may be monovalent, divalent, or polyvalent. 3~7 Examples of cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, [ka] This includes, but is not limited to, the following.

[0142] Unless otherwise specified, "C 4~7 "Cycloalkyl group" refers, either by itself or in combination with other terms, to a saturated cyclic hydrocarbon group consisting of 4 to 7 carbon atoms. 4~7 Cycloalkyl groups include monocyclic or polycyclic groups, and polycyclic groups include spirocyclic rings, fused rings, and crosslinking rings. 4~7 Cycloalkyl groups are C 4~5 , C 4~6 It may contain C4, C5, C6, C7 cycloalkyl groups, and may be monovalent, divalent, or polyvalent. 4~7 Examples of cycloalkyl groups include cyclobutyl group, cyclopentyl group, cyclohexyl group, [ka] This includes, but is not limited to, the following.

[0143] Unless otherwise specified, "C 5~8 "Cross-linked cycloalkyl group" refers to a saturated cross-linked hydrocarbon group consisting of 5 to 8 carbon atoms. 5~8 Crosslinked ring cycloalkyl groups are C 5~6 , C 5~7 , C 5~8 , C 6~7 , C 6~8 or C 7~8 It may contain a crosslinked cycloalkyl group, and may be monovalent, divalent, or polyvalent. 5~8 Examples of crosslinked cycloalkyl groups include: [ka] This includes, but is not limited to, the following.

[0144] Unless otherwise specified, "C 5~8 "Spirocyclic cycloalkyl group" refers to a saturated spirocyclic hydrocarbon group consisting of 5 to 8 carbon atoms. 5~8 Spirocyclic cycloalkyl groups are C 5~6 , C 5~7 , C 5~8 , C 6~7 , C 6~8 or C 7~8 It may contain a spirocyclic cycloalkyl group, and may be monovalent, divalent, or polyvalent. 5~8 Examples of spirocyclic cycloalkyl groups include: [ka] This includes, but is not limited to, the following.

[0145] Unless otherwise specified, the term “4-7 member heterocycloalkyl group” means, by itself or in combination with other terms, a saturated cyclic group consisting of 4-7 ring atoms, wherein 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms, the carbon atoms may optionally be oxo (i.e., C(O)), the nitrogen atoms may optionally be quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 4- to 7-membered heterocycloalkyl groups include monocyclic or polycyclic groups, and the polycyclic groups include spirocyclic rings, fused rings, and crosslinking rings. Furthermore, in the case of the "4- to 7-membered heterocycloalkyl groups," the heteroatoms may occupy the linking positions between the heterocycloalkyl group and the rest of the molecule. The 4- to 7-membered heterocycloalkyl groups include 4- to 5-membered, 4- to 6-membered, 5- to 6-membered, 5- to 7-membered, 4-membered, 5-membered, 6-membered, and 7-membered heterocycloalkyl groups. Examples of 4-7 member heterocycloalkyl groups include pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, tetrahydrothiophenyl group (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl group (including tetrahydrofuran-2-yl, etc.), tetrahydropyran group, piperidinyl group (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl groups, etc.), piperazinyl group (including 1-piperidinyl and 2-piperidinyl groups, etc.), morpholinyl group (including 3-morpholinyl and 4-morpholinyl groups, etc.), dioxanyl group, dithianyl group, isoxazolidinyl group, isothiazolidinyl group, 1,2-oxazine group, 1,2-thiadinyl group, hexahydropyridazine group, homopiperadine group, homopiperidinyl group, [ka] This includes, but is not limited to, the following.

[0146] Unless otherwise specified, "C 5~8The term "cycloalkenyl group" refers to a partially unsaturated cyclic hydrocarbon group consisting of 5 to 8 carbon atoms, containing at least one carbon-carbon double bond, and includes monocyclic and bicyclic systems, the bicyclic system including spiro rings, fused rings, and bridging rings, and all rings in the system are non-aromatic. 5~8 The cycloalkenyl group is C 5~6 , C 5~7 , C 6~7 , C 6~8 , C 7~8 It may contain cycloalkenyl groups, etc., and may be monovalent, divalent, or polyvalent. 5~8 Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl groups.

[0147] Unless otherwise specified, "C 4~7 The term "cycloalkenyl group" refers to a partially unsaturated cyclic hydrocarbon group consisting of 4 to 7 carbon atoms, containing at least one carbon-carbon double bond, and includes monocyclic and polycyclic systems. The polycyclic system includes spiro rings, fused rings, and bridging rings, and all rings in the system are non-aromatic. 4~7 The cycloalkenyl group is C 4~5 , C 5~6 It may contain C4, C5, C6, C7 cycloalkenyl groups, and may be monovalent, divalent, or polyvalent. 4~7 Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl groups.

[0148] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl group" in this invention may be used interchangeably, where "5-6 membered heteroaryl group" refers to a monocyclic group having a conjugated π-electron system consisting of 5-6 ring atoms, where 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p(where p is 1 or 2). The 5-6 membered heteroaryl group may be linked to the rest of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the aforementioned 5-6 member heteroaryl groups include pyrrolyl groups (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups), pyrazolyl groups (including 2-pyrazolyl and 3-pyrazolyl groups), imidazolyl groups (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl groups), oxazolyl groups (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl groups), triazolyl groups (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl). This includes, but is not limited to, azolyl groups (including azolyl groups), tetrazolyl groups, isoxazolyl groups (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl groups), thiazolyl groups (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl groups), furyl groups (including 2-furyl and 3-furyl groups), thienyl groups (including 2-thienyl and 3-thienyl groups), pyridyl groups (including 2-pyridyl, 3-pyridyl, and 4-pyridyl groups), pyrazinyl groups, or pyrimidinyl groups (including 2-pyridinyl and 4-pyridinyl groups).

[0149] Unless otherwise specified, the term “4- to 7-membered heterocycloalkenyl group” means, by itself or in combination with other terms, a partially unsaturated cyclic group consisting of 4 to 7 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3, or 4 of the ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms, the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). 4- to 7-membered heterocycloalkenyl groups include monocyclic or polycyclic groups, and polycyclic systems include spirocyclic rings, fused rings, and bridging rings, with all rings in the system being non-aromatic. Furthermore, with respect to the "4- to 7-membered heterocycloalkenyl groups," heteroatoms can occupy positions where the heterocycloalkenyl group is linked to the rest of the molecule. The 4- to 7-membered heterocycloalkenyl groups include 4- to 5-membered, 4- to 6-membered, 5- to 6-membered, 5- to 7-membered, 4-membered, 5-membered, 6-membered, and 7-membered heterocycloalkenyl groups, etc. Examples of 4- to 7-membered heterocycloalkenyl groups include: [ka] This includes, but is not limited to, the following:

[0150] Unless otherwise specified, the terms “9-10 membered bicyclic heteroaromatic ring” and “9-10 membered bicycloheteraryl group” in this invention may be used interchangeably, where “9-10 membered heteroaryl group” refers to a cyclic group having a conjugated π-electron system consisting of 9 or 10 ring atoms, where 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. This is a bicyclic system, and each ring is aromatic. The nitrogen atom may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p (where p is 1 or 2). A 9- to 10-membered heteroaryl group can be linked to the rest of the molecule via a heteroatom or carbon atom. The 9- to 10-membered bicycloheteraryl group includes, but is not limited to, 9-membered and 10-membered bicycloheteraryl groups. Examples of the 9- to 10-membered bicycloheteraryl group include, but are not limited to, benzimidazolyl, benzopyrazolyl, pyridoimidazolyl, and pyridopyrazolyl groups.

[0151] The compounds of the present invention can be produced by a number of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0152] The structure of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional means of the art. For example, the absolute configuration can be confirmed by single-crystal X-ray diffraction (SXRD), where diffraction intensity data is collected from a cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning is performed using a φ / ω scanning method, the relevant data is collected, and then the crystal structure is further analyzed by a direct method (Shelxs97).

[0153] In this invention, the abbreviations used are as follows: prep-HPLC represents preparative separation by high-performance liquid chromatography, and DPPA represents diphenyl phosphate azide.

[0154] The solvents used in this invention are commercially available. Compounds are named according to general naming conventions in the art or using ChemDraw® software, and for commercially available compounds, the supplier's catalog name is used. [Brief explanation of the drawing]

[0155] [Figure 1] This is a schematic diagram illustrating the bonding between compound A and KCNQ2. [Figure 2] This is a schematic diagram illustrating the bonding between compound B and KCNQ2. [Figure 3] This is a schematic diagram illustrating the bond between compound C and KCNQ2. [Figure 4] This is a schematic diagram illustrating the binding between compound D and KCNQ2. [Figure 5] This is a schematic diagram illustrating the bond between compound E and KCNQ2. [Figure 6] This is a schematic diagram illustrating the binding between compound F and KCNQ2. [Figure 7] This is a schematic diagram illustrating the binding between compound G and KCNQ2. [Modes for carrying out the invention]

[0156] The present invention will be described in detail below with reference to examples, but this does not limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments are disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0157] Calculation example 1 [ka] Glide SP in Maestro (Schrödinger version 2022-1) [1] This was done using the default options. The eutectic structure of KCNQ2 and Retigabine, PDB:7CR2, was selected from the PDB database, and after energy optimization, it was used as the docking template. To prepare the protein, Maestro was used. [2] Using the protein preparation guide module, hydrogen atoms were added, and the ligand was prepared using the OPLS4 force field. The 3D structure of the molecule was generated using LigPrep, and the energy was minimized. [3] The following was performed, and small molecule conformations were sampled using the Confgen module. With Retigabine as the centroid in 7CR2, the side lengths were

number

[0158] [1] Glide, Schrödinger LLC, New York, NY, 2022. [2] Maestro, Schrödinger LLC, New York, NY, 2022. [3] LigPrep, Schrödinger LLC, New York, NY, 2022. Conclusion: The compounds of the present invention bind well to KCNQ2.

[0159] Example 1 [ka] In Step 1, compound 1-1 (10 g, 42.02 mmol) was added to ethanol (200 mL), followed by the addition of compound 1-2 (9.83 g, 50.42 mmol). The mixture was heated to 85°C under nitrogen gas protection and reacted for 12 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 100 / 0~10 / 90, then dichloromethane / methanol = 100 / 0~5 / 95, V / V) to obtain compound 1-3. LCMS (ESI): 335.0 [M+H] + .

[0160] In Step 2, compounds 1-3 (1.14 g, 3.41 mmol) were added to N,N-dimethylacetamide (20 mL), and zinc cyanide (601.01 mg, 5.12 mmol), tetrakis(triphenylphosphine)palladium (197.16 mg, 170.62 μmol), and 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (124.84 mg, 170.62 μmol) were added sequentially. The reaction mixture was heated to 130°C under the protection of nitrogen gas and reacted for 2 hours. After the reaction mixture was cooled to room temperature, it was filtered under reduced pressure, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~50 / 50, V / V) to obtain compounds 1-4. LCMS(ESI): 234.0[M+H] + .

[0161] In step 3, compounds 1-4 (1.5 g, 6.43 mmol) were added to N,N-dimethylformamide (20 mL), cooled to 0°C in an ice bath, then N-bromosuccinimide (1.37 g, 7.72 mmol) was added, and the reaction mixture was heated to 25°C under nitrogen gas protection and reacted for 2 hours. Water (40 mL) was added to the reaction mixture to precipitate the solid, and the mixture was filtered under reduced pressure. The filter cake was collected to obtain compounds 1-5. LCMS (ESI): 312.0 [M+H] + .

[0162] In step 4, compound 1-5 (1 g, 3.20 mmol) was added to methanol (1.5 mL), tetrahydrofuran (3 mL), and water (3 mL). Lithium hydroxide (153.48 mg, 6.41 mmol) was then added, and the reaction mixture was allowed to react at 25°C for 1 hour under the protection of nitrogen gas. After the reaction was complete, hydrochloric acid (10 mL, 2 M) was added dropwise to quench the reaction, followed by the addition of water (100 mL). The mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and evaporated to obtain compound 1-6. LCMS(ESI): 284.1[M+H] + .

[0163] In step 5, compounds 1-6 (270 mg, 950.57 μmol) were added to tert-butanol (5 mL), followed by the sequential addition of N,N-diisopropylethylamine (147.42 mg, 1.14 mmol) and diphenyl phosphate azide (313.91 mg, 1.14 mmol). The reaction mixture was heated to 85°C under nitrogen gas protection and reacted for 12 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 mL) was added to the residue, and the mixture was washed with water (100 mL x 3). The organic phase was collected, washed again with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~20 / 80, V / V) to obtain compounds 1-7. LCMS (ESI): 356.9 [M+H] + .

[0164] In step 6, compound 1-7 (50 mg, 140.78 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added at 0°C. The reaction mixture was allowed to react at 25°C for 1 hour under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain the crude product, water (10 mL) and ethyl acetate (20 mL) were added, the pH was adjusted to alkaline with saturated sodium bicarbonate, washed with water (10 mL x 3), the organic phase was collected, washed again with saturated brine solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~50 / 50, V / V) to obtain compound 1-8. LCMS(ESI): 254.9[M+H] + .

[0165] In step 7, compound 1-8 (35 mg, 137.23 μmol) was added to acetone (4 mL), and N,N-diisopropylethylamine (19.51 mg, 150.95 μmol) and tert-butylacetyl chloride (19.40 mg, 144.09 μmol) were added sequentially at 0°C. The reaction mixture was allowed to react at 25°C for 2 hours under the protection of nitrogen gas. Water (25 mL) was gradually added to the reaction mixture, extracted with ethyl acetate (25 mL x 2), the organic phases were combined and washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~50 / 50, V / V) to obtain compound 1-9. LCMS (ESI): 353.0 [M+H] + .

[0166] In step 8, compounds 1-9 (32 mg, 90.60 μmol) were added to dioxane (5 mL), followed by the addition of p-trifluoromethoxyphenylboronic acid (27.99 mg, 135.90 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (6.63 mg, 9.06 μmol), potassium carbonate (25.04 mg, 181.21 μmol), and water (0.5 mL). The mixture was stirred at 85°C for 2 hours under the protection of nitrogen gas. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by Prep-HPLC (chromatography column: 2_Phenomenex Gemini C18 75×40mm×3μm, mobile phase: [water (ammonia water + ammonium bicarbonate)-acetonitrile], acetonitrile ratio: 50%~80%) to obtain compound 1. LCMS(ESI): 435.0[M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.27(s,1H)7.54(d,J=8.8Hz,2H)7.42(br d,J=8.8Hz,2H)7.11(d,J=8.8Hz,1H)2.20(br s,2H)0.99(s,9H).

[0167] Example 2 [ka] Compound 1-9 (0.11 g, 311.45 μmol) was added to dioxane (5 mL), then p-4-pyridineboric acid (76.56 mg, 622.90 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (35.99 mg, 31.14 μmol), potassium carbonate (86.09 mg, 622.90 μmol), and water (0.5 mL) were added, and the mixture was stirred at 85°C for 2 hours under the protection of nitrogen gas. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by Prep-HPLC (chromatography column: Welch Xtimate C18 150×25mm×5μm, mobile phase: [water (ammonia water + ammonium bicarbonate)-acetonitrile], acetonitrile ratio: 18%~48%) to obtain compound 2. LCMS(ESI): 352.1[M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.84(d,J=4.0Hz,2H),8.40(s,1H),7.94(s,1H),7.43(d,J=5.6Hz,2H),7.16(d,J=8Hz,1H),2.23(s,2H),1.03(s,9H).

[0168] Example 3 [ka] In Step 1, compound 1-5 (1.33 g, 4.26 mmol) was added to dioxane (20 mL), and 2-cyclopentene 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.65 g, 8.52 mmol), tetrakis(triphenylphosphine)palladium (246.22 mg, 213.08 μmol), potassium carbonate (1.18 g, 8.52 mmol), and water (2 mL) were added sequentially. The reaction mixture was heated to 85°C under the protection of nitrogen gas and reacted for 2 hours. Ethyl acetate (200 mL) was added to the reaction mixture, washed with water (200 mL x 3), the organic phase was collected, washed again with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~20 / 80, V / V) to obtain compound 3-1. LCMS(ESI):300.1[M+H] + .

[0169] In Step 2, compound 3-1 (0.95 g, 3.17 mmol) was added to methanol (1.5 mL), tetrahydrofuran (3 mL), and water (3 mL). Lithium hydroxide (152.03 mg, 6.35 mmol) was added, and the reaction mixture was allowed to react at 25°C for 1 hour under the protection of nitrogen gas. After the reaction was complete, hydrochloric acid (10 mL, 2 M) was added dropwise to quench the reaction, followed by the addition of water (100 mL). The mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 3-2. LCMS(ESI): 272.1[M+H] + .

[0170] In step 3, compound 3-2 (0.86 g, 3.17 mmol) was added to tert-butanol (20 mL), and N,N-diisopropylethylamine (491.71 mg, 3.80 mmol) and diphenyl phosphate azide (1.05 g, 3.80 mmol) were added sequentially. The reaction mixture was heated to 85°C under the protection of nitrogen gas and reacted for 6 hours. Ethyl acetate (100 mL) was added to the reaction mixture, washed with water (100 mL x 3), the organic phase was collected, washed again with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~20 / 80, V / V) to obtain compound 3-3. LCMS(ESI): 343.3[M+H] + .

[0171] In step 4, compound 3-3 (0.2 g, 584.17 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added at 0°C. The reaction mixture was allowed to react at 25°C for 1 hour under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain the crude compound, water (10 mL) and ethyl acetate (20 mL) were added, the pH was adjusted to alkaline with saturated sodium bicarbonate, washed with water (10 mL x 3), the organic phase was collected, washed again with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~50 / 50, V / V) to obtain compound 3-4. LCMS(ESI): 243.1[M+H] + .

[0172] In step 5, compounds 3-4 (100 mg, 412.79 μmol) were added to acetone (5 mL), and N,N-diisopropylethylamine (58.68 mg, 454.07 μmol) and tert-butylacetyl chloride (58.34 mg, 433.43 μmol) were added sequentially at 0°C. The reaction mixture was allowed to react at 25°C for 2 hours under the protection of nitrogen gas. Water (50 mL) was gradually added to the reaction mixture, extracted with ethyl acetate (50 mL x 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~50 / 50, V / V) to obtain compound 3. LCMS(ESI): 341.2[M+H] + . 1 H NMR(400MHz,CDCl3)δppm 8.61(m,1H),8.45(s,1H),7.12(d,J=8.4Hz,1H),6.20(s,1H),2.69-2.67(m,4H),2.31(s,2H),2.14-2.07(m,2H),1.10(s,9H).

[0173] Example 4 [ka] In Step 1, compound 1-5 (1 g, 3.20 mmol) was added to dioxane (10 mL), and potassium cyclopropyltrifluoroborate (948.28 mg, 6.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (234.45 mg, 320.42 μmol), and potassium carbonate (885.69 mg, 6.41 mmol) were added sequentially. The reaction mixture was heated to 85°C under the protection of nitrogen gas and reacted for 24 hours. Ethyl acetate (200 mL) was added to the reaction mixture, washed with water (200 mL x 3), the organic phase was collected, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~20 / 80, V / V) to obtain compound 4-1. LCMS (ESI): 274.1 [M+H] + .

[0174] In Step 2, compound 4-1 (0.69 g, 2.53 mmol) was added to methanol (1.5 mL), tetrahydrofuran (3 mL), and water (3 mL). Lithium hydroxide (120.95 mg, 5.05 mmol) was added, and the reaction mixture was allowed to react at 25°C for 1 hour under the protection of nitrogen gas. After the reaction was complete, hydrochloric acid (10 mL, 2 M) was added dropwise to quench the reaction, followed by the addition of water (100 mL). The mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 4-2. LCMS(ESI): 246.1[M+H] + .

[0175] In step 3, compound 4-2 (0.4 g, 1.63 mmol) was added to tert-butanol (10 mL), and N,N-diisopropylethylamine (252.99 mg, 1.96 mmol) and DPPA (538.71 mg, 1.96 mmol) were added sequentially. The reaction mixture was heated to 85°C under the protection of nitrogen gas and reacted for 6 hours. Ethyl acetate (100 mL) was added to the reaction mixture, washed with water (100 mL x 3), the organic phase was collected, washed again with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~20 / 80, V / V) to obtain compound 4-3. LCMS(ESI): 317.1[M+H] + .

[0176] In step 4, compound 4-3 (106 mg, 335.09 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added at 0°C. The reaction mixture was allowed to react at 25°C for 1 hour under the protection of nitrogen gas. The reaction mixture was concentrated to obtain the crude compound. Water (10 mL) and ethyl acetate (20 mL) were added, the pH was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was washed with water (10 mL x 3). The organic phase was collected, and further washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~50 / 50, V / V) to obtain compound 4-4. LCMS(ESI): 217.1[M+H] + .

[0177] In step 5, compound 4-4 (64 mg, 296.00 μmol) was added to acetone (5 mL), and N,N-diisopropylethylamine (42.08 mg, 325.60 μmol) and tert-butylacetyl chloride (43.83 mg, 325.60 μmol) were added sequentially at 0°C. The reaction mixture was allowed to react at 25°C for 2 hours under the protection of nitrogen gas. Water (50 mL) was gradually added to the reaction mixture, extracted with ethyl acetate (50 mL x 2), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 100 / 0~50 / 50, V / V) to obtain compound 4. LCMS(ESI): 315.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ8.51(s,1H),7.80(s,1H),7.06(d,J=8.0Hz,1H),2.34( s, 2H), 2.10-2.01 (m, 1H), 1.15 (s, 9H), 1.14-1.07 (m, 2H), 0.63-0.57 (m, 2H).

[0178] Example 5 [ka] In Step 1, tetrahydrofuran (10 mL), water (40 mL), compound 5-1 (2 g, 10.47 mmol), and zinc cyanide (1.23 g, 10.47 mmol) were added to a 100 mL necked flask and stirred. After purging with nitrogen gas, methanesulfonic acid (2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (831.80 mg, 1.05 mmol) was added, the temperature was raised to 45°C, and the reaction was allowed to proceed for 15 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and ethyl acetate (30 mL x 2) was added for extraction. The resulting organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (V / V petroleum ether:ethyl acetate = 1:0~2:3) to obtain the crude product. Methyl tert-butyl ether (5 mL) was added to the crude product and stirred for 10 minutes, then filtered, and the filtered cake was dried to obtain 5-2. LCMS(ESI): 138.0[M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.19 (s, 1H), 7.43-7.40 (m, 1H), 5.21 (brs, 2H).

[0179] In step 2, compound 5-3 (331.22 mg, 2.63 mmol) was added to dichloromethane (12 mL), and stirring was started. Then, pyridine (941.9 μL, 11.67 mmol), n-butyl anhydrous phosphoric acid (2,4,6-tributyl-1,3,5,2,4,6-trioxatriphosfinan 2,4,6-trioxide, CAS: 163755-62-2, 6.31 g, 8.75 mmol, 50% ethyl acetate solution), and compound 5-2 (400 mg, 2.92 mmol) were added sequentially, and the reaction was carried out at room temperature (15°C) for 48 hours. After adding water (20 mL) and dichloromethane (20 mL) to the reaction system, the mixture was separated, anhydrous sodium sulfate was added to the resulting organic phase, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (V / V petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain compounds 5-4. LCMS (ESI): 246.2 [M + H] + . 1 H NMR (400MHz, CDCl3) δppm 8.50(d,J=1.6Hz,1H),7.75(brs,1H),7.69(dd,J=9.2Hz,1.6Hz,1H),2.86(s,2H),2.54(s,1H),1.87(s,6H).

[0180] In step 3, compound 5-4 (20 mg, 81.55 μmol) was added to chlorobenzene (4 mL), and stirring was started. Then, thionyl chloride (29.61 μL, 407.74 μmol) and pyridine (23.04 μL, 285.42 μmol) were added sequentially, and the temperature was raised to 90°C and the reaction was allowed to proceed for 13 hours. The reaction mixture was concentrated under reduced pressure at 50°C. The crude product was separated and purified by silica gel column chromatography (gradient elution: petroleum ether:ethyl acetate = 100:0~85:15) to obtain compound 5-5. LCMS (ESI): 262.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.38 (s, 1H), 7.05 (dd, J=9.2Hz, 1.2Hz, 1H), 2.77 (s, 1H), 2.49 (s, 6H).

[0181] In step 4, compound 5-5 (50 mg, 191.07 μmol) and compound 5-6 (264.08 mg, 2.29 mmol) were added to dioxane (5 mL), stirring was started, and the mixture was purged with nitrogen gas. Then, cesium carbonate (186.77 mg, 573.22 μmol), potassium iodide (95.15 mg, 573.22 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (34.64 mg, 38.21 μmol) were added sequentially, and the mixture was heated to allow reflux for 3 hours. After the reaction mixture was cooled to room temperature, saturated ammonium chloride (20 mL) solution was added to the reaction system, followed by extraction with ethyl acetate (20 mL x 2 times). The resulting organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (V / V petroleum ether:ethyl acetate = 1:0~1:1) to obtain the crude product. Further separation was performed by preparative high-performance liquid chromatography (chromatography column: WePure Biotech XP tC18 100 mm x 30 mm x 10 μm, mobile phase: A (water, containing 10 mM ammonium bicarbonate) and B (acetonitrile), gradient: B%: 32%~62%) to obtain compound 5. LCMS (ESI): 341.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.42(s,1H),7.33(brs,1H),7.02(d,J=9.2Hz,1H),2.73(s,1H),2.42(s,6H),2.32(s,2H),1.14(s,9H).

[0182] Example 6 [ka] In Step 1, tetrahydrofuran (25 mL), water (100 mL), compound 6-1 (5 g, 20.75 mmol), and zinc cyanide (4.87 g, 41.49 mmol) were added to a 250 mL neck flask and stirred. After purging with nitrogen gas, methanesulfonic acid (2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (1.65 g, 2.07 mmol) was added, the temperature was raised to 45°C, and the reaction was allowed to proceed for 15 hours. Water (50 mL) was added, followed by extraction with ethyl acetate (80 mL x 2). The resulting organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (V / V petroleum ether:ethyl acetate = 1:0~2:3) to obtain the crude product. Methyl tert-butyl ether (10 mL) was then added and the mixture was stirred for 10 minutes. The mixture was filtered, and the filtration cake was dried to obtain compound 6-2. LCMS(ESI): 188.2[M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.50 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 5.53 (s, 2H).

[0183] In step 2, dichloromethane (10 mL), 5-3 (394.39 mg, 3.13 mmol), and N,N-dimethylformamide (129.52 μL, 1.68 mmol) were added to a 100 mL three-necked flask, and stirring was started. After the temperature was lowered to 0°C-5°C, oxalyl chloride (357.88 μL, 4.09 mmol) was added dropwise, and the temperature was raised to room temperature (20°C) and the mixture was reacted for 1 hour. Next, compound 6-2 (450 mg, 2.40 mmol) was added, followed by the addition of 4-dimethylaminopyridine (293.80 mg, 2.40 mmol) and triethylamine (2.01 mL, 14.43 mmol) in dichloromethane (3 mL), and the mixture was reacted at room temperature (15°C) for 18 hours. Saturated ammonium chloride solution (30 mL) and dichloromethane (15 mL) were added to the reaction system, followed by liquid-liquid separation. The resulting organic phase was washed with saturated ammonium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (V / V petroleum ether:ethyl acetate = 1:0~3:2) to obtain compound 6-3. LCMS(ESI): 296.1[M+H] + .

[0184] In step 3, chlorobenzene (36 mL) and compound 6-3 (360 mg, 1.22 mmol) were added to a 100 mL neck flask and stirred. Then, thionyl chloride (442.78 μL, 6.10 mmol) and pyridine (344.44 μL, 4.27 mmol) were added sequentially, and the temperature was raised to 90°C and the reaction was allowed to proceed for 15 hours. The reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (V / V petroleum ether:ethyl acetate = 1:0~17:3) to obtain compound 6-4. LCMS (ESI): 312.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.67 (s, 1H), 7.66 (s, 1H), 2.79 (s, 1H), 2.51 (s, 6H).

[0185] In step 4, compound 5-6 (480.37 mg, 4.17 mmol) and compound 6-4 (130 mg, 417.08 μmol) were added to dioxane (8 mL), stirring was started, and after purging with nitrogen gas, cesium carbonate (407.68 mg, 1.25 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (75.62 mg, 83.42 μmol), and potassium iodide (103.85 mg, 625.62 μmol) were added, the temperature was raised to 120°C, and the reaction was allowed to proceed for 1.5 hours. The reaction mixture was cooled to room temperature, 20 mL of saturated ammonium chloride solution was added to the reaction system, and then ethyl acetate (20 mL x 2) was added for extraction. The resulting organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (V / V petroleum ether:ethyl acetate = 1:0~1:1), and further separated by preparative high-performance liquid chromatography (chromatography column: Waters Xbridge BEH C18 100 mm x 30 mm x 10 μm, mobile phase: A (water, containing 10 mM ammonium bicarbonate) and B (acetonitrile), gradient: B%: 40%~70%) to obtain compound 6. LCMS (ESI): 391.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 8.73 (s, 1H), 7.80 (brs, 1H), 7.62 (s, 1H), 2.74 (s, 1H), 2.40 (s, 6H), 2.35 (s, 2H), 1.13 (s, 9H).

[0186] Example 7 [ka] In Step 1, compound 7-A (10 g, 66.60 mmol) was gradually added to fuming nitric acid (100 mL) in several portions, and the mixture was stirred at 0°C for 8 hours. The reaction mixture was gradually poured into ice water (500 mL) to precipitate the solid, filtered, the filtered cake was collected, and the mixture was dried under reduced pressure to obtain compound 7-B. 1H NMR (CDCl3,400MHz): δppm 8.45(d,J=7.0Hz,1H),7.42(d,J=10.0Hz,1H),3.32-3.20(m,2H),2.97-2.79(m,2H).

[0187] In step 2, compound 7-B (1 g, 5.12 mmol) was added to tetrahydrofuran (15 mL), followed by the addition of cyclobutylamine (400.89 mg, 5.64 mmol) and N,N-diisopropylethylamine (1.99 g, 15.37 mmol). The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 7-C. MS ESI: 246.9 [M+H] + .

[0188] In step 3, compound 7-C (0.9 g, 3.65 mmol) was added to tetrahydrofuran (15 mL), followed by sodium borohydride (207.40 mg, 5.48 mmol), and the mixture was stirred at 0°C for 1 hour. The mixture was diluted with saturated ammonium chloride aqueous solution (20 mL), and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 7-D. MS ESI: 249.0 [M+H] + .

[0189] In step 4, compound 7-D (0.85 g, 3.42 mmol) was added to trifluoroacetic acid (10 mL), followed by the addition of triethylsilane (796.19 mg, 6.85 mmol), and the mixture was stirred at 25°C for 16 hours. The aqueous layer was diluted with sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 7-E. MS ESI: 233.1 [M+H] + .

[0190] In step 5, compound 7-E (0.7 g, 3.01 mmol) was added to ethanol (50 mL) and water (10 mL). Reduced iron powder (841.56 mg, 15.07 mmol) and ammonium chloride (806 mg, 15.07 mmol) were then added, and the mixture was stirred at 90°C for 16 hours. The aqueous layer was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 7-F. MS ESI: 202.9 [M+H] + .

[0191] In step 6, compound 7-F (0.6 g, 2.97 mmol) was added to ethanol (25 mL), followed by the addition of brominated nitrile (628.31 mg, 5.93 mmol), and the mixture was stirred at 25°C for 16 hours. The mixture was diluted with aqueous sodium bicarbonate (50 mL), and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 7-G. MS ESI: 227.9 [M+H] + .

[0192] In step 7, compound 7-G (0.15 g, 0.660 mmol) was added to acetone (20 mL), followed by the addition of N,N-diisopropylethylamine (252.60 mg, 1.95 mmol) and tert-butylacetyl chloride (131.54 mg, 0.977 mmol). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, acetone (10 mL) and aqueous NaOH solution (2N, 20 mL) were added, and the mixture was stirred at 25°C for 1 hour. The mixture was then extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate, 1 / 0~2 / 1, V / V) to obtain compound 7. MS ESI: 326.1 [M+H] + . 1H NMR (DMSO-d6,400MHz): δppm 10.26(brs,1H),7.55(br s,1H),7.35(s,1H),4.73(br s,1H),3.00-2.85(m,4H),2.84-2.54(m,2H),2.33(br s,2H),2.26(s,2H),2.09-2.02(m,2H),1.94(q,J=10.2Hz,1H),1.86-1.74(m,1H),1.05(s,9H).

[0193] Example 8 [ka] In Step 1, compound 8-1 (6 g, 26.20 mmol) was added to trifluoroacetic acid (30 mL), triethylsilane (9.14 g, 78.59 mmol) was added, and the reaction mixture was allowed to react for 24 hours at a controlled temperature of 25°C under the protection of nitrogen gas. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture to adjust the pH to 7-8, extracted with ethyl acetate (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and rotated-dried under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0, V / V) to obtain compound 8-2.

[0194] In step 2, a lithium diisopropylamide mixed solution of tetrahydrofuran n-heptane (2M, 22.32 mL) was added to tetrahydrofuran (30 mL), and after cooling to -78°C, compound 8-2 (6.4 g, 29.76 mmol) was added and stirred and reacted for 30 minutes. Then, N,N-dimethylformamide (89.28 mmol, 6.87 mL) was added, and the reaction mixture was raised to 25°C under the protection of nitrogen gas and reacted for 30 minutes. Saturated ammonium chloride solution (500 mL) was added dropwise to the reaction mixture, extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and rotated-dried under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0~5 / 1, V / V) to obtain compound 8-3.

[0195] In step 3, compound 8-3 (5 g, 20.57 mmol) was added to a mixed solution of water (50 mL) and tert-butanol (50 mL). After cooling to 0°C, sodium chlorite (7.44 g, 82.26 mmol), sodium dihydrogen phosphate (9.87 g, 82.28 mmol), and 2-methyl-2-butene (205.70 mmol, 21.79 mL) were added, and the reaction mixture was maintained at 0°C under the protection of nitrogen gas for 2 hours. The reaction mixture was extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and rotated-dried under reduced pressure to obtain compound 8-4. LCMS(ESI): 259.0[M+H] + .

[0196] In step 4, compound 8-4 (1.7 g, 6.56 mmol) was added to tert-butanol (17 mL), and after cooling to 0°C, N,N-diisopropylethylamine (1.37 mL) and diphenyl phosphate azide (2.17 g, 7.87 mmol) were added. The reaction mixture was heated to 80°C under the protection of nitrogen gas and reacted for 2 hours. The reaction mixture was rotated dry under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0~20 / 1, V / V) to obtain compound 8-5. LCMS(ESI): 232.0[M-Boc+H] + . 1 H NMR (400MHz, CDCl3) δppm 7.24 (s, 1H), 5.95 (s, 1H), 2.89-2.94 (m, 4H), 2.09-2.16 (m, 2H), 1.51 (s, 9H).

[0197] In step 5, compound 8-5 (0.4 g, 1.21 mmol) was added to dioxane (5 mL), and cyclobutylamine (2.42 mmol, 207.61 μL), methanesulfonic acid (2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (219.63 mg, 242.28 μmol), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (260.10 mg, 484.57 μmol), and potassium tert-butoxide (271.87 mg, 2.42 mmol) were added. The reaction mixture was heated to 100°C under the protection of nitrogen gas and reacted for 2 hours. The reaction mixture was rotated dry under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0~20 / 1, V / V) to obtain compound 8-6. LCMS(ESI): 221.1[M+H] + .

[0198] In step 6, compound 8-6 (0.266 g, 1.21 mmol) was added to ethanol (5 mL), cyanogen bromide (2.42 mmol, 177.27 μL) was added, and the reaction mixture was maintained at 25°C under nitrogen gas protection for 1 hour. The reaction mixture was rotated dry under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol, 100 / 0~20 / 1, V / V) to obtain compound 8-7. LCMS(ESI): 246.0[M+H] + .

[0199] In step 7, compound 8-7 (55 mg, 179.38 μmol) was added to acetone (5 mL), N,N-diisopropylethylamine (34.37 μL) was added, and the reaction mixture was cooled to 0°C under the protection of nitrogen gas. Then, tert-butylacetyl chloride (27.41 μL) was added dropwise, and the reaction mixture was maintained at 25°C under the protection of nitrogen gas for 1 hour. The reaction mixture was filtered under reduced pressure, the filtrate was collected, and the mixture was rotated dry under reduced pressure. Methanol (5 mL) and 10% sodium hydroxide aqueous solution (2 mL) were added, and the mixture was stirred and reacted for 1 hour. After rotating dry under reduced pressure, the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and rotated dry under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate, 100 / 0~10 / 1, V / V) to obtain compound 8. LCMS(ESI): 344.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.36(s,1H),7.44(s,1H),4.70-4.79ppm(m,1H),3.03(t,J=7.2Hz,2H),2.96(t,J=7.2Hz,2H),2.72-2.85ppm(m,2H), 2.38-2.40ppm(m,2H),2.29(s,2H),2.11-2.13ppm(m,2H),1.92-1.97ppm(m,1H),1.81-1.86ppm(m,1H),1.066(s,9H).

[0200] Example 9 [ka] In Step 1, compound 9-1 (10 g, 66.60 mmol) was added to fuming nitric acid (100 mL) in several portions and reacted with stirring at 0°C for 8 hours. The reaction mixture was gradually poured into ice water (500 mL), filtered, and the filtered cake was collected and dried under reduced pressure to obtain compound 9-2. 1 H NMR (400MHz, CDCl3) δppm 8.44 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 10.4 Hz, 1H), 3.27 (t, J = 6.0 Hz, 2H), 2.81-2.84 (m, 2H).

[0201] In step 2, compound 9-2 (1 g, 5.12 mmol) was added to tetrahydrofuran (15 mL), followed by the addition of 1-methylcyclobutylamine hydrochloride (972.00 mg, 6.15 mmol) and N,N-diisopropylethylamine (2.68 mL). The reaction mixture was maintained at 25°C and stirred for 16 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9-3. LCMS(ESI): 261.1[M+H] + .

[0202] In step 3, compound 9-3 (0.5 g, 1.92 mmol) was added to trifluoroacetic acid (5 mL), triethylsilane (613.63 μL) was added, and the reaction mixture was allowed to react for 24 hours under nitrogen gas protection at a controlled temperature of 25°C. The reaction mixture was then controlled to 0°C, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7-8, extracted with ethyl acetate (50 mL x 2), washed with saturated saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and rotated-dried under reduced pressure to obtain compound 9-4.

[0203] In step 4, compound 9-4 (0.8 g, 3.25 mmol) was added to ethanol (40 mL) and water (10 mL), and then reduced iron powder (907.01 mg) and ammonium chloride (868.68 mg) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9-5.

[0204] In step 5, compound 9-5 (0.7 g, 3.24 mmol) was added to ethanol (10 mL), and then brominated nitrile (685.51 mg, 6.47 mmol) was added. The reaction mixture was stirred and allowed to react for 12 hours at a controlled temperature of 25°C. After dilution with ethyl acetate (50 mL), 10% sodium bicarbonate aqueous solution (50 mL) was added to quench the mixture. The aqueous phase was extracted with ethyl acetate (50 mL x 2), and the combined organic phase was washed with saturated brine (50 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated to obtain compound 9-6.

[0205] In step 6, tert-butylacetyl chloride (209.16 mg, 1.55 mmol, 215-85 μL) was added to acetone (10 mL), followed by the addition of N,N-diisopropylethylamine (541.30 μL) and compound 9-6 (0.25 g, 1.04 mmol), and the mixture was stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was added to acetonitrile (5 mL), and sodium hydroxide aqueous solution (1 M, 4.57 mL) was added. The reaction mixture was stirred and allowed to react for 2 hours at a controlled temperature of 25°C. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated by pre-HPLC (column type: C18 100 × 40 mm, mobile phase: [H2O(TFA)-ACN), gradient: 23%~53% ACN, 8 min) to obtain compound 9. LCMS (ESI): 340.1 [M + H] + . 1 H NMR(400MHz,CDCl3)δppm 6.93-7.13(m,2H),2.95(t,J=6.8Hz,4H),2.76-2.90(m,2H),2.52(t,J=8.0Hz,2H) ,2.31(s,2H),2.06-2.20(m,2H),1.86-2.06(m,3H),1.67(s,3H),1.07ppm(s,9H).

[0206] Example 10 [ka] In Step 1, compound 9-2 (1 g, 5.12 mmol) was added to tetrahydrofuran (20 mL), and then tert-butylamine (592.32 μL) and N,N-diisopropylethylamine (2.68 mL) were added. The reaction mixture was maintained at 25°C and stirred for 16 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 10-1.

[0207] In step 2, compound 10-1 (0.5 g, 2.01 mmol) was added to trifluoroacetic acid (5 mL), triethylsilane (965.00 μL) was added, and the reaction mixture was allowed to react for 24 hours under nitrogen gas protection at a controlled temperature of 25°C. The reaction mixture was then controlled to 0°C, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7-8, extracted with ethyl acetate (50 mL x 2), washed with saturated saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and rotated-dried under reduced pressure to obtain compound 10-2. LCMS(ESI): 179.1[M+H] + . 1 H NMR (400MHz, CDCl3) δppm 7.95 (s, 1H), 6.66 (s, 1H), 2.84 (q, J=7.2Hz, 4H), 2.06-2.10 (m, 2H), 0.98 (s, 1H).

[0208] In step 3, compound 10-2 (0.1 g, 426.82 μmol) was added to ethanol (30 mL) and water (8 mL), and then iron powder (119.19 mg, 2.13 mmol) and ammonium chloride (114.15 mg, 2.13 mmol) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. The mixture was diluted with water (200 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 10-3.

[0209] In step 4, compound 10-3 (0.3 g, 1.47 mmol) was added to ethanol (5 mL), and then brominated nitrile (311.06 mg, 2.94 mmol) was added. The reaction mixture was stirred and allowed to react for 12 hours at a controlled temperature of 25°C. The reaction mixture was rotated dry under reduced pressure to obtain the crude product. The crude product was separated by pre-HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [H2O(NH3.H2O+NH4HCO3)-ACN], gradient: 33%~63% ACN, 8 min) to obtain compound 10-4.

[0210] In step 5, tert-butylacetyl chloride (16.66 μL) was added to acetone (10 mL), followed by the addition of N,N-diisopropylethylamine (20.89 μL) and compound 10-4 (25 mg, 109.02 μmol), and the mixture was stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was added to acetonitrile (5 mL), and aqueous sodium hydroxide solution (1 M, 4.57 mL) was added. The reaction mixture was stirred at a controlled temperature of 25°C for 2 hours, water (20 mL) was added, and it was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated by pre-HPLC (column type: Welch Xtimate C18 150×25mm×5μm, mobile phase: [H2O(NH3H2O+NH4HCO3)-ACN), gradient: 58%~88% ACN, 8 min) to obtain compound 10. LCMS(ESI): 328.2[M+H] + . 1 H NMR(400MHz,CDCl3)δppm 7.53(s,1H),7.23-7.05(m,1H),2.92-3.01(q,J=7.2Hz,4H),2.39(s,2H),2.13(t,J=7.6Hz,2H),1.93(s,9H),1.07ppm(s,9H).

[0211] Biological Tests Experimental Example 1: Thallium Flow Analysis Test using hKCNQ2 / 3 Experimental Objective: In a stable hKCNQ2 / 3 CHO cell line, the in vitro concentration-response relationship of compounds was investigated using FLIPR thallium flux.

[0212] Regarding experimental cells and reagents, (1) Cell line: hKCNQ2 / 3 CHO cells were stably transfected.

[0213] (2) The cell culture reagents include F12 medium, fetal bovine serum FBS (10%), penicillin-streptomycin (Invitrogen, catalog number 15140-122), and G418 (Invitrogen, catalog number 10131027).

[0214] (3)Cell culture: The cell line was passaged three times weekly at a passage ratio of 1:2 to 1:3. When the cells proliferated to confluence >80% in the T-75 cell bottle, they were digested with 0.25% trypsin-EDTA solution for approximately 1 minute, transferred from the cell bottle, and passaged. Depending on the passage ratio, the cells were transferred to another T-75 cell bottle containing complete cell growth medium. Note: To maintain logarithmic cell proliferation, it was necessary to maintain cell proliferation in a subconfluent monolayer state. Cells were passaged every 2-3 days, depending on the time it took for the cells to double.

[0215] Experimental flow: (1) Day 1, cell preparation: Cells were digested using the method described above, and cell density and vitality were measured using Cell Countess. The volume of the single-cell suspension was adjusted with complete cell growth medium. Next, hKCNQ2 / 3_CHO cells were inoculated into 384-well plates pre-coated with PDL at a density of approximately 20,000 cells / well (30 μL / well). The plates were then incubated overnight in an incubator at 37°C with 5% CO2 humid air.

[0216] (2) The following day, preparation of the compound: The compound to be measured was diluted to its storage concentration with dimethyl sulfoxide (DMSO) and stored in a refrigerator at -20°C. The compound addition program was set on the liquid workstation ECHO, and the compound was added to the plate using the liquid workstation ECHO. Retigabine (RTG) was used as a positive reference, with a maximum concentration of 100 μM, and was diluted 3-fold for a total of 9 dose dilutions. 5 mM K + and 1mM Tl + The plates were supplemented with a buffer solution containing [the specified substance].

[0217] Note: 1) K2SO4 and Tl2SO4 were prepared in 1× chloride-free buffer. If the voltage-dependent potassium channels are different, Tl + and K + The concentration needed to be adjusted. + The concentration is approximately 0.5 mM to 5 mM, K + The concentration was set to approximately 5 mM to 30 mM. 2) K2SO4 and Tl2SO4 were prepared with 2 mM K per 1 mM solution. + and Tl + It contained [unclear], and the final concentration had to be calculated from the ion concentration. 3) TlCl precipitates easily, so a chloride-free buffer solution had to be used.

[0218] (3) The next day, experimental test: After the cells reached confluence, the cell analysis plate was removed from the incubator. Prepare the experimental buffer, Tl + The dye was diluted (molecular instrument #R8222). The culture medium was discarded using the Bravo liquid workstation, and 25 μL of Tl was added to each well. + Dye was added. After incubation for 1 hour, the tip of the cell analysis plate, composite plate, and FLIPR were removed. TETRA FLIPR detection was performed using Molecular Devices (USA). After needle tip placement, baseline was read at 60 seconds, then 12.5 μL was added from the composite plate (3×) to the cell measurement plate, and data was recorded simultaneously for at least 5 minutes.

[0219] (4) Data processing: The maximum signal was generated using FLIPR software. Data analysis was performed using Excel (2013) and Prism 6.01. Data quality was controlled to S / B > 2.00 and Z coefficient > 0.50. IC 50 or EC 50 This was defined as the median line between the lowest-ranking and highest-ranking platforms, and was calculated using Prism 6.01 and a 4-parameter logistic model.

[0220] The experimental results are shown in Table 1.

[0221] Table 1. Experimental results of the agonist activity of the compounds of the present invention against hKCNQ2 / 3. [Table 2] Conclusion: The compounds of the present invention have clear agonist activity against KCNQ2 / 3.

[0222] Experimental Example 2: Evaluation of behavioral and pharmacodynamic studies of target compounds in a model of epilepsy induced by maximal electric shock. Experimental objective: This study used the behavioral studies of male CD-1 mice to detect the effects of the target compounds on the convulsive behavior of acute mouse epilepsy induced by maximum electric shock.

[0223] Experimental materials: Male CD-1 mice (25g-35g) from Beijing Weitong Lihua Laboratory Animals Co., Ltd., raised on standard feed as laboratory animals.

[0224] Experimental process: After the experimental animals arrived at the animal laboratory facility, they needed at least one week to adapt. The physical condition of the mice was observed daily, and they were randomly divided into groups based on body weight one day before administration. One hour before electrical stimulation, each group was orally administered a different dose of the target compound. On the day of the experiment, the corneas of male CD-1 mice in each group were anesthetized locally with 2% lidocaine. Then, electrical stimulation was applied to the corneas of the mice using silver bipolar electrodes with a pulse width of 18 mA, 60 Hz, a pulse width of 0.6 ms, and a stimulation duration of 1 s to induce convulsive behavior. Subsequently, the latency period of epileptic seizures and the duration of limb rigidity after electrical stimulation were observed, and the seizure protection rate for each group was statistically calculated.

[0225] The experimental results are shown in the table below.

[0226] Table 2 Test results of the pharmacodynamics of the compounds of the present invention [Table 3] Experimental conclusion: The compounds of the present invention exhibit good anticonvulsant activity in an epilepsy model induced by maximal electric shock.

[0227] Experimental Example 3: Pharmacokinetic Evaluation of Compounds Experimental objective: This study aims to evaluate the pharmacokinetic behavior of compounds after a single intravenous injection and intragastric administration, to consider their bioavailability after intragastric administration, and to provide animal study data for clinical research.

[0228] Experimental materials: CD-1 mouse (male, 7-9 weeks old) Experimental procedure: The pharmacokinetic characteristics of compounds administered intravenously and orally to rodents were tested according to a standard protocol. In the experiments, candidate compounds were prepared as clear solutions and administered to mice by single intravenous injection and orally. The intravenous and oral solvents were mixed solvents prepared with 5% DMSO / 60% PEG400 / 35% water. In this study, four female CD-1 mice and two mice were administered the drug intravenously, and plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The other two mice were administered the drug orally via gastric injection, and plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The samples were stirred at 3200 × g for 10 minutes at 4°C, and the supernatant was separated to obtain plasma samples. A 20-fold volume methanol solution containing an internal standard containing precipitated protein was added, and the samples were stirred at 12000 × g for 15 minutes. The samples were then centrifuged at 4°C, and 50 μL of the supernatant was transferred to a 96-well plate for secondary centrifugation. The supernatant was then injected into the samples, and the drug blood concentration was quantitatively analyzed by LC-MS / MS analysis. Pharmacokinetic parameters, such as the peak concentration (C), were then analyzed. max ), clearance (CL), half-life (T 1 / 2 ), tissue distribution (Vdss), area under the drug-time curve (AUC) 0-last ), bioavailability (F), etc., were calculated.

[0229] The experimental results are shown in Table 3.

[0230] Table 3. Test results of the pharmacokinetics of the compound of the present invention. [Table 4] Experimental conclusion: The compounds of the present invention possess good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life, and clearance.

[0231] Experimental Example 4: Evaluation of Plasma Protein Binding Rate Experimental objective: The protein binding rates of the compounds were measured in CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and human plasma using equilibrium dialysis.

[0232] Experimental materials: Commercialized plasma, two-layer dialysis membrane, and equilibrium dialysis machine.

[0233] Experimental procedure: The two-layer dialysis membrane was immersed in ultrapure water for approximately one hour, removed, divided into two, and either immersed in an ethanol:water (20:80, v:v) solution for 20 minutes or left at 2-8°C. The shelf life was one month. Before starting the experiment, the dialysis membrane was rinsed twice with ultrapure water and immersed in ultrapure water for 20 minutes to prepare it for use.

[0234] On the day of the experiment, cryopreserved CD-1 mouse, Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human plasma were thawed in flowing cold tap water. After the plasma was completely thawed, it was centrifuged at 3220 × g for 5 minutes, and the suspensions and precipitates were removed. The pH value of the plasma was measured, and either plasma with a pH in the range of 7.4 ± 0.1 was used directly, or plasma adjusted with 1% phosphoric acid or 1 M sodium hydroxide to a pH in the range of 7.4 ± 0.1 was used.

[0235] Plasma sample preparation process: 3 μL of compound or warfarin working solution was added to each of the five blank plasma samples described above (597 μL each) and thoroughly mixed to obtain a plasma sample (n=1) with a compound concentration of 2 μM and a warfarin concentration of 2 μM. The concentration of the organic phase DMSO was set to 0.5%. The sample was thoroughly mixed before proceeding to the next step.

[0236] Preparation process for T0 samples: 50 μL of plasma samples containing the compound and warfarin were transferred to sample receiving plates (n=3), 50 μL of blank PBS was immediately added, and then 500 μL of stop solution was added to the T0 samples of the compound and warfarin. The samples were stored at 2-8°C and subsequently processed together with the other dialyzed samples.

[0237] Plasma sample dialysis process: 100 μL of compound (2 μM) and warfarin (2 μM) plasma samples were added to the administration end (n=3) of each dialysis well, and 100 μL of blank PBS was added to the corresponding receiving end of the dialysis well. The dialysis plates were placed in a 5% CO2 incubator and incubated with shaking at 37°C at approximately 100 rpm for 4 hours.

[0238] After dialysis, 50 μL of post-dialysis PBS samples and post-dialysis plasma samples (n=3) were transferred to a new 96-well plate (sample receiving plate). Each sample well was then filled to a final volume of 100 μL, with a plasma-to-PBS volume ratio of 1:1, by adding the corresponding volume of blank plasma or PBS. All samples underwent protein precipitation before being analyzed by LC-MS / MS.

[0239] The formulas for calculating the unbound rate (%Unbound), bound rate (%Bound), and recovery rate (%Recovery) of a compound are as follows:

[0240] %Unbound=100×F / T %Bound=100-%Unbound %Recovery=100×(F+T) / T0 In the formula, F is the concentration of the dialysis-receiving end compound, T is the concentration of the dialysis-supply end compound, and T0 is the concentration of the compound in the plasma at time zero.

[0241] The experimental results are shown in Table 4.

[0242] Table 4 Test results of plasma protein binding rate of the compound of the present invention [Table 5] Experimental conclusion: The compound of the present invention has an appropriate plasma protein binding rate.

[0243] Experimental Example 5: Permeability Evaluation Experimental objective: This study aims to evaluate the P-gp substrate of compounds in MDR1-MDCKI cells.

[0244] Experimental materials: MDR1-MDCKI cell line.

[0245] Experimental procedure: Transport Experiment: The test samples, nadolol and metoprolol were administered at a concentration of 2.00 μM, and digoxin at a concentration of 10.0 μM. The samples were administered bidirectionally (AB and BA directions), and each administration concentration was repeated twice. The administration solution, recipient solution, and transport buffer were pre-incubated in a 37.0°C water bath for 30 minutes. The cell layer was washed twice with transport buffer. The administration solution and recipient solution were added to the corresponding cell plate wells (75.0 μL and 250 μL of sample were added to the apical and basal wells, respectively). After adding the samples, the cell plates were incubated in an incubator at 37.0°C, 5.0% CO2, and saturated humidity for 90 minutes. The initial administration solution was designated as the T0 sample. After 90 minutes of incubation, samples were collected from each well and labeled as AB recipient end, BA recipient end, AB administration end, and BA administration end, respectively. After sample collection, all samples were mixed with appropriate volumes of transport buffer and stop solution. After vortexing all samples, they were centrifuged at 3220 × g and 20.0 °C for 10 minutes. An appropriate volume of supernatant was transferred to a sample analysis plate, and after sealing the plate, the samples were stored at 2.0–8.0 °C if not analyzed immediately. Analysis was performed by LC-MS / MS.

[0246] Cell membrane integrity test: After the transport experiment was completed, the integrity of the MDR1-MDCKII cell layer was detected using a fluorescent yellow detection experiment (Lucifer Yellow Rejection Assay). The remaining solution in the apical and basal wells was removed, and 75.0 μL of transport buffer containing 100 μM fluorescent yellow was added to the apical well, and 250 μL of transport buffer was added to the basal well. The cell plate was incubated in a cell incubator at 37.0°C, 5.0% CO2, and saturated humidity for 30 minutes. Then, 20.0 μL of sample was collected from the apical well and mixed with 60.0 μL of transport buffer, and 80.0 μL of sample was collected from the basal well. The relative fluorescence intensity (relative fluorescence unit, RFU) was detected by microplate reader at 425 / 528 nm (excitation / emission) spectra.

[0247] In this study, sample analysis of the compounds and control compounds, nadolol, metoprolol, and digoxin, was performed using LC-MS / MS. Retention times of analytes and internal standards, chromatogram collection, and chromatogram integration were processed using the software Analyst (Sciex, Framingham, MA, USA). Sample analysis did not include standard curves or quality control samples, and semi-quantitative detection was performed using the ratio of the peak area of ​​the analyte to the peak area of ​​the internal standard.

[0248] Using the following formula, the apparent permeability coefficient (P app The following were calculated: efflux rate (ER), efflux rate (cm / s), and solution recovery rate (%).

[0249]

number

[0250]

number

[0251] The experimental results are shown in Table 5.

[0252] Table 5 Test results of compound permeability of the present invention [Table 6] Experimental conclusion: The compounds of the present invention have good permeability properties.

[0253] Experimental Example 6: Solubility Evaluation Experimental objective: This experiment aims to measure the kinetic solubility of compounds when incubated for 24 hours at room temperature in a 50 mM phosphate buffer solution at pH levels (2.0, 6.5, and 7.4) using the direct ultraviolet method.

[0254] Experimental procedure: 10 μL of DMSO storage solution of the test compound and the control compound were added to a 96-well plate, and 490 μL of the test medium was added to each 96-well plate. The plate was sealed and vortexed for 2 minutes. The sample incubation concentration was 200 μM, and the DMSO ratio was 2%. The 96-well plate was placed in a plate shaker and incubated at a rotation speed of 800 rpm for 24 hours at room temperature to achieve solubility equilibrium. After incubation, the sample was placed in a centrifuge and centrifuged at a rotation speed of 4000 rpm for 10 minutes at 25°C. The supernatant of the centrifuged sample was transferred to a filter plate and centrifuged at a rotation speed of 4000 rpm for 5 minutes, and filtered to obtain the filtrate. LC-UV linear quantitative analysis was performed on the concentration of the filtrate (sample dilution was performed as necessary).

[0255] Experimental data was acquired and processed using Empower software. Linear regression analysis was performed by plotting the relationship between peak areas and their concentrations in μM.

[0256] The experimental results are shown in Table 6.

[0257] Table 6 Test results of the solubility of the compounds of the present invention [Table 7] Experimental conclusion: The compounds of the present invention have appropriate solubility.

[0258] Experimental Example 7: Evaluation of Liver Microsome Stability Experimental objective: This study aims to evaluate the one-phase metabolic stability of the test product in CD-1 mice, Sprague-Dawley (SD) rats, beagle dogs, cynomolgus monkeys, and human liver microsomes.

[0259] Experimental materials: The animal and human liver microsomes used in this test system are purchased from Xenotech, Corning, or other qualified suppliers.

[0260] Experimental procedure: Preparation of buffer solution: 73.21 g of dipotassium hydrogen phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate were dissolved in 4000 mL of ultrapure water. The pH of the solution was adjusted to 7.40 ± 0.10 with 10.0% phosphoric acid or 1.00 M potassium hydroxide, and the final concentration was 100 mM.

[0261] Preparation of working fluid: The test sample powder was prepared as a 10.0 mM storage solution with DMSO, and then further diluted with a suitable organic solvent. The control compounds testosterone, diclofenac, and propafenone were prepared as 10.0 mM storage solutions with DMSO, and then further diluted with a suitable organic solvent.

[0262] Preparation of liver microsome solution: Microsomes of various genera were diluted in 100 mM potassium phosphate buffer to a working solution of 0.56 mg / mL. The final concentration of microsomes in the reaction system was set to 0.500 mg / mL. Detailed preparation methods are described in the experimental record.

[0263] Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) solution: An appropriate amount of reduced nicotinamide adenine dinucleotide phosphate was dissolved in magnesium chloride solution and mixed homogeneously by shaking. In the reaction system, NADPH with a final concentration of 1.00 mM and magnesium chloride with a final concentration of 1.00 mM were obtained. Detailed preparation methods are described in the experimental record.

[0264] Preparation of stop solution: A stop solution was prepared using acetonitrile containing internal standards (toluenesulfonyl and labelol). The prepared stop solution was stored in a refrigerator at 2.0–8.0°C. Detailed preparation methods are described in the experimental log.

[0265] Incubation Process: Two 96-well incubation plates were prepared and named the T60 incubation plate and the NCF60 incubation plate, respectively. 445 μL of microsome activator (with a liver microsomal protein concentration of 0.56 mg / mL) was added to each of the T60 and NCF60 incubation plates, and the incubation plates were pre-incubated at 37°C for approximately 10 minutes. After pre-incubation, 5 μL of the test sample or control compound activator was added to each of the T60 and NCF60 incubation plates and mixed uniformly. 50 μL of potassium phosphate buffer was added to each well of the NCF60 incubation plate to initiate the reaction. 180 μL of stop solution (acetonitrile solution containing 250 nM tolbutamide and 250 nM labetalol) and 6 μL of NADPH activator were added to the T0 stop plate, and 54 μL of sample was transferred from the T60 incubation plate to the T0 stop plate (T0 sample generation). The reaction was initiated by adding 44 μL of NADPH activator to each well of a T60 incubation plate. Only 54 μL of microsome activator, 6 μL of NADPH activator, and 180 μL of stop solution were added to a Blank plate. Therefore, in the test or control compound samples, the final reaction concentrations of the compound, testosterone, diclofenac, and propafenone were 1 μM, the liver microsome concentration was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively. After incubation for an appropriate time (e.g., 5, 15, 30, 45, and 60 minutes), 180 μL of stop solution (acetonitrile solution containing 250 nM tolbutamide and 250 nM labetalol) was added to the sample well of each stop plate, and then 60 μL of the sample was removed from the T60 or NCF60 incubation plate to stop the reaction. All sample plates were shaken uniformly and centrifuged at 3220 × g for 20 minutes. 80 μL of supernatant was then taken from each well, diluted in 240 μL of pure water, and used for liquid chromatography-tandem mass spectrometry.

[0266] Data analysis: Sample analysis of compounds in this study was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS), and standard curves and quality control samples were not included. Semi-quantitative detection was performed using the ratio of the analyte peak area to the internal standard peak area. Retention times of the analyte and internal standard, chromatogram collection, and chromatogram integration were processed using the software Analyst (Sciex, Framingham, Massachusetts, USA).

[0267] The coefficient of variation (CV) of the peak area of ​​the internal standard in each matrix for each analysis batch was set to within 20%.

[0268] The peak height of the highest concentration sample was set to 2.00 × 10⁶ cps (using API 4000 or API 5500) or 4.00 × 10⁷ cps (using API 6500 or API 6500Plus) or less. The peak height of the internal standard was set to 2.00 × 10⁶ cps (using API 4000 or API 5500) or 4.00 × 10⁷ cps (using API 6500 or API 6500Plus) or less.

[0269] The in vitro elimination rate constant ke for the compound and the control compound was determined by converting the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard in the following equation into a persistence rate.

number

[0270]

number

[0271] CLint(mic) = 0.693 / T1 / 2 / Microsomal protein content (microsomal concentration mg / mL during incubation) CLint(liver) = CLint(mic) × Microsomal protein content in the liver (mg / g) × Ratio of liver weight to body weight In vivo liver clearance (CL(liver)) was estimated based on a well-stirred model.

[0272] CL(liver)=(CLint(liver)×fu×Qh) / (CLint(liver)×fu+Qh) The fu (free fraction in blood) was defaulted to being equal to 1.

[0273] The experimental results are shown in Table 7.

[0274] Table 7 Stability test results for liver microsomes of the compound of the present invention [Table 8] Experimental conclusion: The compounds of the present invention have good liver microsomal stability.

[0275] Experimental Example 8: Evaluation of Drug Interactions Experimental objective: The inhibitory effects of compounds on the activity of human liver microsomal cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A) were evaluated using a cocktail method with specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

[0276] Experimental materials: Human liver microsomes, probe substrates, positive control inhibitors, and reduced nicotinamide adenine dinucleotide phosphate.

[0277] Experimental procedure: 20 μL of substrate solution was added to the corresponding wells of the reaction plate, and 20 μL of potassium phosphate buffer was added to the blank wells.

[0278] Two μL of the test compound and positive control working solution were added to the corresponding wells, and two μL of solvent was added to the inhibitor-free well and the blank well.

[0279] Human liver microsomal agonist was prepared, and 158 μL of the human liver microsomal agonist was added to each well of the reaction plate.

[0280] The reaction plate was preheated to 37.0°C for 10 minutes.

[0281] 20 μL of NADPH cofactor agonist solution was added to the reaction plate to start the reaction.

[0282] The mixture was mixed in a 37.0°C water bath and incubated for 10 minutes. After that, 400 μL of stop solution was added to the reaction plate to stop the reaction.

[0283] The sample plate was placed in a centrifuge and centrifuged at 4000 rpm for 20 minutes.

[0284] 200 μL of the supernatant was taken out, an appropriate 100 μL of dilution with pure water was added, and the mixture was shaken until uniformly mixed.

[0285] Analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0286] Data analysis: The residual activity percentage is used as the y-coordinate, and the test substance concentration as the x-coordinate. A nonlinear regression analysis is performed using 3 or 4 parameters in XL fit software to determine the IC of the test substance. 50 The values ​​were calculated. The IC obtained by fitting with XL fit software. 50 If the dose is greater than the maximum dose (50.0 μM), or if IC 50 If the IC cannot be fitted, 50 The value is labeled as ">50.0 μM".

[0287] 3-parameter equation:

number

number

[0288] Table 8 Test results of compound-drug interactions of the present invention [Table 9] Experimental conclusion: The compounds of the present invention have relatively low CYP inhibitory activity and a low risk of drug interaction.

[0289] Experimental Example 9: Testing of hERG potassium channel activity using a fully automated patch-clamp (Qpatch) system. Experimental method: CHO-hERG cells 175cm 2 The cells were cultured in a culture flask and, after growing to a cell density of 60%-80%, the culture medium was removed, the mixture was washed once with 7 mL of PBS (phosphate buffer), and then digested with 3 mL of cell dissociation reagent. After complete digestion, the mixture was neutralized with 7 mL of culture medium, then centrifuged, the supernatant was aspirated, and the mixture was resuspended in 5 mL of culture medium to achieve a cell density of 2-5 × 10⁶. 6 The volume was set to / mL.

[0290] The compound mother liquor was diluted with DMSO, and 10 μL of the compound mother liquor was added to 20 μL of DMSO solution, diluting it sequentially threefold to six different DMSO concentrations. 4 μL of each of the six DMSO concentrations of the compound was added to 396 μL of extracellular fluid, diluting it 100-fold to six intermediate concentrations. Further, 80 μL of each of the six intermediate concentrations of the compound was added to 320 μL of extracellular fluid, diluting it five-fold to the final concentration to be tested. The highest test concentration was 40.00 μM, followed sequentially by six concentrations of 40.00, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content at the final test concentration was less than 0.2%, and this concentration of DMSO did not affect hERG potassium channels. The entire dilution process for compound preparation was completed using Bravo instruments.

[0291] The electrophysiological processes were recorded, and the processes of single-cell high-resistance sealing and whole-cell mode formation were all completed automatically using the Qpatch instrument. After the whole-cell recording mode was established, the cells were fixed at -80 millivolts, and a pre-voltage of -50 millivolts was applied for 50 milliseconds before applying a depolarizing stimulus of +40 millivolts for 5 seconds. Then, the cells were repolarized to -50 millivolts and maintained for 5 seconds, and then returned to -80 millivolts. This voltage stimulus was applied every 15 seconds and recorded for 2 minutes, followed by recording for 5 minutes for the extracellular fluid. Administration was then started, beginning with the lowest test concentration of the compound, and recording for 2.5 minutes for each test concentration. At least 3 cells (n≧3) were tested for each concentration.

[0292] Data analysis: The experimental data was analyzed using GraphPad Prism 5.0 software, and the results are shown in Table 9.

[0293] Table 9 IC2 for hERG potassium channels of the compounds of the present invention 50 Test results [Table 10] Experimental conclusion: The compounds of the present invention do not have a significant inhibitory effect on hERG potassium channels and have a low risk of cardiotoxicity.

Claims

1. A compound represented by formula (I) or (V), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, Ring A is selected from 9-10 membered bicycloheteraryl groups. Ring B is fused with ring A, and ring B is C ４～７ Cycloalkyl groups, C ４～７ Selected from cycloalkenyl groups, 4- to 7-membered heterocycloalkyl groups, and 4- to 7-membered heterocycloalkenyl groups, each R １ is each independently selected from H, F, Cl, Br, I, OH, NH ２ , CN, CF ３ , C ２～４ alkyl group, C １～４ alkoxy group, C ３～７ cycloalkyl group and 4 to 7-membered heterocycloalkyl group, wherein said C ２～４ alkyl group, C １～４ alkoxy group, C ３～７ cycloalkyl group and 4 to 7-membered heterocycloalkyl group are each independently optionally substituted with 1, 2 or 3 R ａ , R ２ C is a cyclobutyl group. ５～８ Crosslinked ring cycloalkyl group, C ５～８ Spirocyclic cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups, 4-7 membered heterocycloalkyl groups, and C ５～８ Selected from cycloalkenyl groups, the cyclobutyl group, C ５～８ Crosslinked ring cycloalkyl group, C ５～８ Spirocyclic cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups, 4-7 membered heterocycloalkyl groups, and C ５～８ Each cycloalkenyl group can independently have any 1, 2, or 3 R groups. ｂ Replaced by, R ３ H and -C(O)C １～４ Selected from alkyl groups, R ４ C １～６ alkyl group, C １～６ Alkoxy group, -CH ２ -C ３～７ Cycloalkyl groups, -CH ２ - Selected from 4 to 7 member heterocycloalkyl groups, the C １～６ alkyl group, C １～６ Alkoxy group, -CH ２ -C ３～７ Cycloalkyl groups, -CH ２ - Each of the 4- to 7-membered heterocycloalkyl groups can independently have 1, 2, 3, 4, or 5 R groups. ｃ Replaced by, Each R ５ These are H, F, Cl, Br, I, =O, and C, respectively, independently. １～４ Alkyl and C １～４ Selected from alkoxy groups, the C １～４ Alkyl and C １～４ Each alkoxy group can be independently substituted with one, two, or three halogens. Each R ６ These are H, F, Cl, Br, I, CN, and C, respectively, independently. １～４ alkyl group, C １～４ Alkoxy group, C ３～７ Selected from cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, and phenyl groups, the C １～４ alkyl group, C １～４ Alkoxy group, C ３～７ The cycloalkyl group, the 4- to 7-membered heterocycloalkyl group, and the phenyl group each independently may have 1, 2, or 3 R groups. ６ａ Replaced by, Each R ａ and R ｃ These are H, F, Cl, Br, I, OH, and NH, respectively, independently. ２ , CN, CH ３ and CF ３ Selected from, Each R ｂ These are H, F, Cl, Br, I, =O, OH, NH, each independently. ２ , CN, C １～４ Alkyl and C １～４ Selected from alkoxy groups, the C １～４ Alkyl and C １～３ Each alkoxy group can be independently substituted with one, two, or three fluorine atoms. Each R ６ａ These are H, F, Cl, Br, I, OH, and NH, respectively, independently. ２ , CN, C １～４ Alkyl and C １～４ Selected from alkoxy groups, the C １～４ Alkyl and C １～４ Each alkoxy group can be independently substituted with any 1, 2, 3, 4, or 5 fluorine atoms. m is selected from 1, 2, 3, and 4. p and q are independently selected from 1, 2, and 3, As a condition, 1) R ２ The group is selected from a phenyl group and a 5-6 membered heteroaryl group, and the phenyl group and the 5-6 membered heteroaryl group each independently have 1, 2, or 3 R groups. ｂ If replaced by, structural fragment 【Chemistry 2】 teeth, 【Transformation 3】 Selected from, or, 2) R ２ R is selected from cyclobutyl groups, and the cyclobutyl groups are arbitrarily 1, 2, or 3 ｂ When replaced, m is selected from 2, 3, and 4.

2. Each R ａ Each of these is independently selected from H, F, and OH, and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Each R ｂ These are H, F, =O, and CH, respectively, independently. ３ and OCF ３ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

4. Each R ｃ These are H, F, and CH, respectively, independently. ３ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

5. Each R １ is each independently selected from H, F, Cl, OH, NH ２ , CN, CF ３ , CH ２ CH ３ , CH ２ CH ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ , OCH(CH ３ ) ２ , cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group, and the aforementioned CH ２ CH ３ , CH ２ CH ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ , OCH(CH ３ ) ２ , cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group and azacyclobutyl group are each independently optionally substituted with 1, 2 or 3 R ａ , or each R １ is each independently selected from H, F, CN, CF ３ , 【Chemistry 4】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

6. R ２ The group is selected from cyclobutyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentyl, phenyl, pyrazolyl, thiazolyl, pyridyl, oxetanyl, azacyclobutyl, piperidinyl, piperazinyl, cyclopentenyl, and cyclohexenyl groups, and each of the cyclobutyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentyl, phenyl, pyrazolyl, thiazolyl, pyridyl, oxetanyl, azacyclobutyl, piperidinyl, piperazinyl, cyclopentenyl, and cyclohexenyl groups can be independently and optionally have 1, 2, or 3 R groups. ｂ Replaced by, or R ２ teeth, 【Transformation 5】 Selected from, or R ２ teeth, 【Transformation 6】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. Each R ４ is CH ２ CH ３ , CH ２ CH ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , CH ２ C(CH ３ ) ３ , OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ , OCH(CH ３ ) ２ , 【Transformation 7】 is selected from, and said CH ２ CH ３ , CH ２ CH ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , CH ２ C(CH ３ ) ３ , OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ , OCH(CH ３ ) ２ , 【Transformation 8】 Each of these can independently have any 1, 2, 3, 4, or 5 R ｃ Replaced by, or R ４ teeth, 【Chemistry 9】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

8. Structural unit 【Chemistry 10】 teeth, 【Chemistry 11】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

9. Structural unit 【Chemistry 12】 teeth, 【Chemistry 13】 Selected from, in the formula, R ５ , R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein p is as defined in claim 1.

10. Structural unit 【Chemistry 14】 teeth, 【Chemistry 15】 A compound according to claim 9 or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 11】 【Chemistry 16】 Selected from, During the ceremony, Each R １ These are H, F, CN, and CF, respectively, independently. ３ , 【Chemistry 17】 Selected from, R ２ C ５～８ Crosslinked ring cycloalkyl group, C ５～８ Spirocyclic cycloalkyl groups, 4- to 7-membered heterocycloalkyl groups, and C ５～８ Selected from the cycloalkenyl groups, the C ５～８ Crosslinked ring cycloalkyl group, C ５～８ Spirocyclic cycloalkyl groups, 4- to 7-membered heterocycloalkyl groups, and C ５～８ Each cycloalkenyl group can independently have any 1, 2, or 3 R groups. ｂ Replaced by, R ４ teeth, [Chemistry 18] A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 12】 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 A compound or a pharmaceutically acceptable salt thereof, as shown in [reference].

13. A pharmaceutical composition comprising a therapeutic or prophylactic effective amount of a compound according to any one of claims 1 to 12, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable adjuvant.

14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the manufacture of a drug for treating Kv7 potassium ion channel opener-related disorders.

15. The use according to claim 14, wherein the Kv7 potassium ion channel opener-related disease is selected from epilepsy, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorder, stroke, Alzheimer's disease, neurodegenerative disease, neuronal hyperexcitability, complications of cocaine abuse, nicotine withdrawal syndrome, alcohol withdrawal syndrome, or tinnitus.

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