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CN-122029154-A - Heteroaryl derivatives and uses thereof

CN122029154ACN 122029154 ACN122029154 ACN 122029154ACN-122029154-A

Abstract

Disclosed are heteroaryl derivatives and application thereof, and particularly discloses compounds shown in formulas (I) and (V) or pharmaceutically acceptable salts thereof.

Inventors

  • CHEN SHUHUI
  • HE HAIYING
  • LI PENG
  • ZHANG HONGBO
  • GAO NA

Assignees

  • 深圳市康哲生物科技有限公司

Dates

Publication Date
20260512
Application Date
20240927
Priority Date
20230928

Claims (15)

  1. A compound represented by the formula (I) or (V) or a pharmaceutically acceptable salt thereof, Wherein, the Ring a is selected from 9-10 membered bicyclic heteroaryl; Ring B is fused to ring a, ring B being selected from the group consisting of C 4-7 cycloalkyl, C 4-7 cycloalkenyl, 4-7 membered heterocycloalkyl, and 4-7 membered heterocycloalkenyl; each R 1 is independently selected from H, F, cl, br, I, OH, NH 2 、CN、CF 3 、C 2-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, each of which is independently optionally substituted with 1, 2, or 3R a , C 2-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl; R 2 is selected from cyclobutyl, C 5-8 bridged cycloalkyl, C 5-8 spirocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, and C 5-8 cycloalkenyl, each independently optionally substituted with 1,2, or 3R b ; R 3 is selected from H and-C (O) C 1-4 alkyl; R 4 is selected from C 1-6 alkyl, C 1-6 alkoxy, -CH 2 -C 3-7 cycloalkyl, -CH 2 -4-7 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, -CH 2 -C 3-7 cycloalkyl, -CH 2 -4-7 membered heterocycloalkyl each independently being optionally substituted with 1,2,3, 4 or 5R c ; Each R 5 is independently selected from H, F, cl, br, I, = O, C 1-4 alkyl and C 1-4 alkoxy, each of which is independently optionally substituted with 1,2 or 3 halogens; Each R 6 is independently selected from H, F, cl, br, I, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and phenyl, each of which is independently optionally substituted with 1, 2, or 3R 6a , C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, and phenyl; Each R a and R c is independently selected from H, F, cl, br, I, OH, NH 2 、CN、CH 3 and CF 3 ; Each R b is independently selected from H, F, cl, br, I, =o, OH, NH 2 、CN、C 1-4 alkyl, and C 1-4 alkoxy, each of which C 1-4 alkyl and C 1-3 alkoxy is independently optionally substituted with 1,2, or 3F; each R 6a is independently selected from H, F, cl, br, I, OH, NH 2 、CN、C 1-4 alkyl and C 1-4 alkoxy, each of which C 1-4 alkyl and C 1-4 alkoxy is independently optionally substituted with 1,2,3,4 or 5F; m is selected from 1,2, 3 and 4; p and q are each independently selected from 1,2 and 3; Provided that the conditions are that, 1) When R 2 is selected from phenyl and 5-6 membered heteroaryl, each of which is independently optionally substituted with 1,2 or 3R b , structural fragments Selected from the group consisting of Or alternatively 2) When R 2 is selected from cyclobutyl optionally substituted by 1,2 or 3R b , m is selected from 2,3 and 4.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from H, F and OH.
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from H, F, = O, CH 3 , and OCF 3 .
  4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R c is independently selected from H, F and CH 3 .
  5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 1 is 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, cyclobutyl, cyclopentyl, oxetanyl and azetidinyl, each of 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, cyclobutyl, cyclopentyl, oxetanyl and azetidinyl is independently optionally substituted with 1, 2 or 3R a , or each R 1 is independently selected from H, F, CN, CF 3 ,
  6. The compound of claim 1, wherein R 2 is selected from cyclobutyl, spiro [3.3] heptyl, bicyclo [1.1.1] pentyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, cyclopentenyl and cyclohexenyl, said cyclobutyl, spiro [3.3] heptyl, bicyclo [1.1.1] pentyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, cyclopentenyl and cyclohexenyl being each independently optionally substituted with 1,2 or 3R b , or R 2 is selected from Or R 2 is
  7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from 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 、 The 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 、 Each independently optionally substituted with 1, 2, 3,4 or 5R c , or R 4 is selected from
  8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from the group consisting of
  9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from the group consisting of Wherein R 5 、R 6 and p are as defined in claim 1.
  10. A compound according to claim 9, or a pharmaceutically acceptable salt, structural unit thereof Selected from the group consisting of
  11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of, Wherein, the Each R 1 is independently selected from H, F, CN, CF 3 , R 2 is selected from the group consisting of C 5-8 bridged cycloalkyl, C 5-8 spirocycloalkyl, 4-7 membered heterocycloalkyl, and C 5-8 cycloalkenyl, each of which is independently optionally substituted with 1,2, or 3R b ; R 4 is selected from
  12. A compound shown below or a pharmaceutically acceptable salt thereof,
  13. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 12, stereoisomers thereof, and pharmaceutically acceptable salts 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, for the manufacture of a medicament for the treatment of a disease associated with a Kv7 potassium channel opener.
  15. The use according to claim 14, wherein the Kv7 potassium channel opener-related disease is selected from epilepsy, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorders, cerebral stroke, alzheimer's disease, neurodegenerative diseases, neuronal hyperexcitability states, complications resulting from cocaine abuse, nicotine withdrawal syndrome, alcohol withdrawal syndrome or tinnitus.

Description

Heteroaryl derivatives and uses thereof The present invention claims the following priorities: 1) priority and equity of chinese patent application number 202311284906.6 submitted to the chinese national intellectual property office at 28 of 9 of 2023, 2) priority and equity of chinese patent application number 202311410637.3 submitted to the chinese national intellectual property office at 26 of 10 of 2023, 3) priority and equity of chinese patent application number 202311849240.4 submitted to the chinese national intellectual property office at 28 of 12 of 2023, 4) priority and equity of chinese patent application number 202410539834.3 submitted to the chinese national intellectual property office at 29 of 4 of 2024, and 5) priority and equity of chinese patent application number 202411320022.6 submitted to the chinese national intellectual property office at 20 of 9 of 2024, the disclosures of which are incorporated herein by reference in their entirety. Technical Field The invention relates to heteroaryl derivatives and application thereof, in particular to compounds shown in formulas (I) and (V) or pharmaceutically acceptable salts thereof. Background Voltage-gated Kv7/KCNQ potassium ion channels are widely present in the nervous system and play an important role in regulating neuronal excitability. The research on Kv7 potassium ion channel openers provides a wide space for the research and development of new drugs for treating diseases related to nerve hyperexcitability, such as epilepsy and pain. There are 5 subtypes of the Kv7 family, of which Kv7.2 and Kv7.3 (encoded by KCNQ2 and KCNQ 3) are homologous subunits forming widely expressed neuronal voltage-gated potassium channels, key subunits involved in neuronal signaling and regulating epileptic hyperexcitatory states. KCNQ2 and KCNQ3 are mainly distributed in the brain and are highly expressed in the cerebellar cortex, amygdala, caudate nucleus and hippocampus, forming homotetramers/heterotetramers (M-type potassium ion channels), which are the molecular basis for M-current formation. The increase in M current can hyperpolarize the cell membrane, thereby reducing neuronal excitability and preventing the occurrence and propagation of action potential bursts and the resulting attacks. Enhancing the open state of kv7.2/kv7.3 channels in neurons favors hyperpolarized resting states (RESTING STATE), reduces spikes in rapid motor potential (i.e., burst discharge), stabilizes the resting membrane potential of neurons, and thus limits the excitability of neurons, which is also responsible for the antiepileptic effects. Retigabine has proved that KCNQ2/3 potassium ion channel opener is excellent in clinic for treating convulsion and epilepsy, so that development of KCNQ2/3 opener has become a hot spot problem for clinically treating neurological diseases such as epilepsy. XEN1101, a company of biopharmaceutical, has entered clinical stage 3 for the treatment of focal seizures. The BHV-7000 of Biohaven company also has completed clinical phase 1 experiment, obviously reduces related side effects, and is a very promising drug for treating nervous systems such as epilepsy and pain. Disclosure of Invention The invention provides compounds represented by the formulas (I) and (V) or pharmaceutically acceptable salts thereof, Wherein, the Ring a is selected from 9-10 membered bicyclic heteroaryl; Ring B is fused to ring a, ring B being selected from the group consisting of C 4-7 cycloalkyl, C 4-7 cycloalkenyl, 4-7 membered heterocycloalkyl, and 4-7 membered heterocycloalkenyl; each R 1 is independently selected from H, F, cl, br, I, OH, NH 2、CN、CF3、C2-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, each of which is independently optionally substituted with 1, 2, or 3R a, C 2-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl; R 2 is selected from cyclobutyl, C 5-8 bridged cycloalkyl, C 5-8 spirocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, and C 5-8 cycloalkenyl, each independently optionally substituted with 1,2, or 3R b; R 3 is selected from H and-C (O) C 1-4 alkyl; R 4 is selected from C 1-6 alkyl, C 1-6 alkoxy, -CH 2-C3-7 cycloalkyl, -CH 2 -4-7 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, -CH 2-C3-7 cycloalkyl, -CH 2 -4-7 membered heterocycloalkyl each independently being optionally substituted with 1,2,3, 4 or 5R c; Each R 5 is independently selected from H, F, cl, br, I, = O, C 1-4 alkyl and C 1-4 alkoxy, each of which is independently optionally substituted with 1,2 or 3 halogens; Each R 6 is independently selected from H, F, cl, br, I, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and phenyl, each of said C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, and phenyl being independently optionally substituted with 1, 2, or 3R 6a; Each R b is independently selected from H, F, cl, br, I, =o, OH, NH 2、CN、C1