Search

EP-4735423-A1 - KV7 MODULATORS

EP4735423A1EP 4735423 A1EP4735423 A1EP 4735423A1EP-4735423-A1

Abstract

The present invention provides novel compounds (I) which modulate the K v 7 potassium channels. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders responsive to the activation of K v 7 potassium channels.

Inventors

  • LARSEN, JANUS S.
  • AMRUTKAR, Dipak
  • BROWN, DAVID TRISTRAM
  • DYHRING, TINO
  • CHRISTOPHERSEN, PALLE
  • JACOBSEN, Thomas Amos
  • POULSEN, Pernille Hartveit
  • Strøbæk, Dorte
  • BODDUM, Jessica Klein

Assignees

  • Saniona A/S

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1 . A compound according to formula (I): formula (I) or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein, R° is selected from the group consisting of -OH, and -CH3; R 1 is aryl optionally substituted with one or more, identical or different, substituents R 4 , or heteroaryl optionally substituted with one or more, identical or different, substituents R 4 ; R 4 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, halogen and CN; R 2 is selected from the group consisting of -H, -CH3, and -CF3; R 3 is selected from the group consisting of -H and -OH; A is of formula (II): formula (II) wherein A 1 is C-R 5 or N; R 5 is -H or halogen; A 2 is C-R 6 ; R 6 is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more F; C1-5 alkyl optionally substituted with one or more F; halogen; and N(R 10 )(R 11 ); R 10 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 12 ; R 11 is -H; R 12 is selected from the group consisting of halogen, C3-5 cycloalkyl and C1-3 alkyl; A 3 is C-R 7 or N; R 7 is selected from the group consisting of -H, halogen and C1-5 alkyl; A 4 is C-R 8 or N; R 8 is selected from the group consisting of -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, and -CN; A 5 is C-R 9 or N; R 9 is -H or halogen; with the proviso that the compound is not /V-[1-(3,5-Difluorophenyl)cyclopropyl]-p-methyl-1/7-imidazole-1-propanamide; N-[1-(3-Chlorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide; N-[1-(3-Fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide; or 3-Fluoro-N-[1-(3-fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide.
  2. 2. The compound according to claim 1 , wherein the compound is of formula (Illa): formula (Illa)
  3. 3. The compound according to claim 1 , wherein the compound is of formula (111 b) : formula (I I lb)
  4. 4. The compound according to any one of the preceding claims, wherein R 1 is phenyl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, thiazol-2-yl or thiazol-5-yl optionally substituted with one or more, identical or different substituents R 4 selected from the group consisting of -F, -Cl, -Br, C1-5 alkoxy, C1-5 alkyl, and -CN.
  5. 5. The compound according to any one of claims 1 to 3, wherein R 1 is phenyl substituted with one or more, identical or different, substituents R 4 selected from the group consisting of -F, -Cl, -Br, C1-5 alkoxy, C1-5 alkyl, and -CN.
  6. 6. The compound according to any one of claims 1 to 3, wherein R 1 is phenyl substituted with one or more, identical or different, substituents R 4 selected from the group consisting of -F, -Br, C1-5 alkyl, and -CN.
  7. 7. The compound according to any one of claims 1 to 3, wherein R 1 is phenyl substituted with one or more -F.
  8. 8. The compound according to any one of claims 1 to 3, wherein R 1 is pyridinyl substituted with one or more, identical or different, substituents R 4 selected from the group consisting of -F, -Cl, -Br, C1-5 alkoxy, C1-5 alkyl, and -CN.
  9. 9. The compound according to any one of claims 1 to 3, wherein R 1 is pyridinyl substituted with one or more, identical or different, substituents R 4 selected from the group consisting of -F, -Cl, -Br, and C1-5 alkoxy.
  10. 10. The compound according to any one of claims 1 to 3, wherein R 1 is thiazolyl substituted with one or more, identical or different substituents R 4 selected from the group consisting of -F, -Cl, -Br, and C1-5 alkyl.
  11. 11 . The compound according to any one of claims 1 to 3, wherein R 1 is thiazolyl substituted with one or more, identical or different substituents R 4 selected from the group consisting of -F, -Cl, -Br, and C1-5 alkyl,
  12. 12. The compound according to any one of claims 1 to 3, wherein R 1 is indolyl substituted with one or more, identical or different substituents R 4 selected from the group consisting of -F, -Cl, -Br, and C1-5 alkyl.
  13. 13. The compound according to any one of claims 1 to 3, wherein R 1 is selected from:
  14. 14. The compound according to any one of the preceding claims, wherein R 2 is -CH 3 and R° is -OH.
  15. 15. The compound according to any one of the preceding claims, wherein R° is - OH, R 2 is -CH 3 , and R 3 is -H.
  16. 16. The compound according to any one of claims 1 to 12, wherein R 2 is -CF3 and R° is -OH.
  17. 17. The compound according to any one of the preceding claims, wherein R 3 is -H.
  18. 18. The compound according to any one of the preceding claims, wherein A is of formula (II), formula (II) wherein: a) A 1 is C-R 5 ; A 2 is C-R 6 ; A 3 is C-R 7 ; A 4 is C-R 8 ; and A 5 is C-R 9 , or b) A 1 is N; A 2 is C-R 6 ; A 3 is C-R 7 ; A 4 is C-R 8 ; and A 5 is C-R 9 , or c) A 1 is C-R 5 ; A 2 is C-R 6 ; A 3 is N; A 4 is C-R 8 ; and A 5 is C-R 9 , or d) A 1 is C-R 5 ; A 2 is C-R 6 ; A 3 is C-R 7 ; A 4 is N; and A 5 is C-R 9 , or e) A 1 is N; A 2 is C-R 6 ; A 3 is N; A 4 is C-R 8 ; and A 5 is C-R 9 , or f) A 1 is C-R 5 ; A 2 is C-R 6 ; A 3 is C-R 7 ; A 4 is C-R 8 ; and A 5 is N.
  19. 19. The compound according to any one of the preceding claims, wherein R 5 is -H or -F, R 6 is -CF 3 , -Cl, -Br, -CH 3 -OCH 2 CF 3 , -OCF 3 , -OCH 3 , -OCH 2 CF 2 H, - R 8 is -H, -F, -Cl, - Br, -CN, -CF 2 H, cyclopropyl, or -OCH 3 . R 9 is -H or -F.
  20. 20. The compound according to any one of the preceding claims, wherein A 1 is C(H), A 2 is C(OCH 2 CF 3 ) and A 5 is C(H).

Description

Kv7 modulators Technical field The present invention provides novel compounds which modulate the Kv7 potassium channels. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders responsive to the activation of Kv7 potassium channels. Background Kv7 channels are voltage-dependent potassium channels that conduct potassium ions (K+) across cell membranes in response to depolarizations of the cell membrane potential. The Kv7 channel family consists of five proteins Kv7.1 , Kv7.2, Kv7.3, Kv7.4, Kv7.5 which are encoded by the human genes KCNQ1 , KCNQ2, KCNQ3, KCNQ4 and KCNQ5 or the rodent, dog or non-human primate equivalents. The Kv7 proteins have the traditional Kv structure with six transmembrane helixes (S1-S6) and with the N and C termini located intracellularly. Functional Kv7 channels exists as homo- or hetero- tetrameric complexes of these subunits surrounding the K+ conducting transmembrane pore. Functional heteromeric channels described are Kv7.2/Kv7.3, Kv7.4/Kv7.3, Kv7.5/Kv7.3, and Kv7.4/Kv7.5 (for a general Kv7 review, see Soldovieri et al 2011 ; Physiology, 26, 365-376). Kv7.2-Kv7.5 has been detected in neurons of the central nervous system (CNS), where especially the Kv7.2/Kv7.3 heteromeric channel plays an important role and underlies the so-called M-current (Brown and Adams, 1980; Nature, 283(5748), 673-676) a sustained and acetylcholine-sensitive K+ current active in the range of action potential initiation and therefore a dominant conductance controlling neuronal excitability. The specific roles of Kv4 and Kv7.5 containing channels in the CNS seems less clear, but their wider expression, also in peripheral tissues such as smooth muscle cells, make especially Kv7.4 a potential off-target for development of Kv7 modulators for neuronal indications (Svaloe et al 2011 ; Basic & Clinical Pharmacology & Toxicology, 110, 145-153). Kv7 channels are also expressed in primary sensory neurons and are thus targets for treatment of various pain conditions. In contrast to the neuronally expressed Kv7 channels, Kv7.1 is primarily expressed in cardiac cells and in some epithelia, typically in complex with different KCNE p-subunits. The pivotal role of the Kv7.2/Kv7.3 channel in controlling the excitability of CNS neurons is well illustrated by the mutations in both KCNQ2 and KCNQ3, which is strongly linked to neonatal or pediatric epilepsy diseases ranging in severity from relative benign self- limiting cases to serious encephalopathies, whereas such associations are seen much less frequently for Kv7.5 and hardly ever for Kv7.4 (Maljevic and Lerche, 2014; Progress in Brain Research, 213, 17-53). In line with this, compounds with an activating effect on the neuronal Kv7 channels have for a long time been known as anti-epileptics and analgesics, exemplified by the drugs retigabine, which was registered for the management of treatment resistant focal epilepsies, and flupirtine, which was on the market as an analgesic in some countries including Germany. Retigabine and flupirtine are close chemical analogues and both have now been withdrawn from the marked due to long-term toxicities related to their unstable chemical structures (both are anilines) (Bock and Link, 2019; Future Med Chem, 11(4), 337-355). In addition to these chemical problems retigabine also showed adverse effects including both CNS and peripheral tissues of which the risk of causing urinary retention in sensitive patients was probably the most severe (Brickel et al, 2012; Epilepsia, 53(4), 606-612). Retigabine continued in new Ph 3 studies controlled by Xenon Pharmaceuticals under the name Xen496 with children diagnosed with KCNQ2 encephalopathies, but these studies were discontinued in May 2023 for yet unknown reasons. Since Kv7 activation is a clinically validated concept (with no drugs currently on the marked) for both epilepsy and pain, there is great interest in developing new Kv7 activators based on alternative chemical scaffolds. Fortunately, the scientific and patent literature reveals that other chemical classes can also act as Kv7 channel activators, either by interaction with the traditional retigabine activator site in the pore region (S5-6) or with an alternative site in the voltage sensor domains (S1-4). An added benefit of new chemical scaffolds may also be the possibility for better differentiation between Kv7 subtypes and thereby potentially improved efficacy and safety of the medicines. Approximately 1/3 of the epilepsy population is still not adequately treated with the existing medications. Similarly, several chronic pain conditions are poorly managed, which has led to the escalating opioid crisis in the USA. Thus, novel treatment principles are urgently needed for these diseases and improved Kv7 channel activating medicines represent a possible step to resolve these health issues. Summary In one aspect, the present disclosure provides