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EP-4739669-A1 - SODIUM CHANNEL BLOCKERS

EP4739669A1EP 4739669 A1EP4739669 A1EP 4739669A1EP-4739669-A1

Abstract

The present disclosure relates to sulfonamide compounds, the use thereof for modulat-ing the sodium channel Nav1.5 and methods of treating or preventing diseases, disorders, or conditions using the same.

Inventors

  • DAY, ROBERT FRANCIS
  • SMITH, NICHOLA
  • WU, Yanxiang
  • TANG, HAIHAO
  • DORÉ, Michael
  • GAMPE, Christian Michael
  • GAO, XIANG
  • FRIEDMAN, ADAM
  • GULGEZE EFTHYMIOU, HATICE BELGIN
  • HARRISON, Tyler
  • KING, Sandra Marie
  • LARROW, JAY FRANCIS
  • LAU, Sii Hong
  • PATEL, Tajesh
  • PENG, YUNSHAN

Assignees

  • Novartis AG

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. A compound of formula (I) : or a pharmaceutically acceptable salt thereof, wherein ring A is: R 1 is selected from -OH and C 1-4 -alkyl; R 2 is selected from H and C 1-4 -alkyl optionally substituted with one or more halogen atoms; R 3 is selected from H and C 1-4 -alkyl; R 4 is selected from H and C 1-4 -alkyl optionally substituted with -OH; R 5 is phenyl substituted with (i) at least one group selected from halogen, C 1-4 -alkyl, -O-C 1-4 -alkyl, and O-C 3-6 -cy-cloalkyl, wherein the C 1-4 -alkyl is optionally substituted with one or more halogen atoms, or (ii) two adjacent groups bonded together to form a 4-to 7-membered heterocyclyl containing two or more heteroatoms selected from O, S and N, wherein the 4-to 7-membered heterocyclyl is optionally substituted with one or more halogen at-oms; R 6 is H or a halogen atom; Y 1 is selected from CH, N and O; Y 2 is CH or N; Y 3 is CH or N; and Y 4 is CH or N, wherein at least one of Y 1 , Y 2 , Y 3 and Y 4 is N.
  2. A compound according to claim 1, wherein R 1 is -OH or -CH 3 ; R 2 is selected from H, -CH 3 , -CH 2 CH 3 and -CF 3 ; R 3 is H or -CH 3 ; R 4 is selected from H, -CH 3 and -CH 2 OH; R 5 is phenyl substituted with (i) at least one group selected from F, Cl, -CF 3 , -OCF 3 , -OCH 2 CF 3 , and -O-cyclopro-pyl, or (ii) two adjacent groups bonded together to form and R 6 is selected from H, F and Cl.
  3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
  4. A compound according to any one of claims 1 to 3, said compound being of formula (II-A) or (II-B) : or a pharmaceutically acceptable salt thereof.
  5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each of Y 1 , Y 2 , Y 3 and Y 4 are N; or Y 2 is CH and each of Y 1 , Y 3 and Y 4 are N; or each of Y 1 and Y 2 are CH and each of Y 3 and Y 4 are N.
  6. A compound according to any one of claims 1 to 5, said compound being of formula (III-A) or (III-B) : or a pharmaceutically acceptable salt thereof.
  7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 is H.
  8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH.
  9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, -CH 3 and -CH 2 CH 3 .
  10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH and R 2 is -CH 3 .
  11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl substituted with at least two groups selected from F, Cl, -CF 3 , -OCF 3 and -OCH 2 CF 3 .
  12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 5 is: wherein, R 5a and R 5b are independently selected from F, Cl, -CF 3 , -OCF 3 and -OCH 2 CF 3 .
  13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 5 is:
  14. A compound according to any one of claims 1 to 13, said compound being of formula (IV-A) or (IV-B) : or a pharmaceutically acceptable salt thereof.
  15. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypro-pane-1-sulfonamide; 2-hydroxy-2- (6- (2- ( (2, 2, 5-trifluorobenzo [d] [1, 3] dioxol-4-yl) methyl) -2H-tetrazol-5-yl) pyri-din-2-yl) propane-1-sulfonamide; 2- (2-fluoro-5- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) phenyl) -2-hydroxy-propane-1-sulfonamide; 2- (4-chloro-3- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) phenyl) -2-hydroxy-propane-1-sulfonamide; 2- (4-fluoro-3- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) phenyl) -2-hydroxy-propane-1-sulfonamide; 2- (2-fluoro-3- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) phenyl) -2-hydroxy-propane-1-sulfonamide; 3- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -3-hydroxy-butane-2-sulfonamide; 2- (6- (2- (2, 5-difluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfona-mide; 2- (6- (2- (2-fluoro-5- (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypro-pane-1-sulfonamide; 2- (6- (2- (5-chloro-2-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfon-amide; 2- (3-fluoro-5- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) phenyl) -2-hydroxy-propane-1-sulfonamide; 2- (3- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) phenyl) -2-hydroxypropane-1-sulfonamide; 2- (5-chloro-6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hy-droxypropane-1-sulfonamide; 2- (6- (2- (2-fluoro-5- (2, 2, 2-trifluoroethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; 3- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -1-hydroxy-butane-2-sulfonamide; 2- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-pyrazol-3-yl) pyridin-2-yl) -2-hydroxy-butane-1-sulfonamide; 2- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-pyrazol-3-yl) pyridin-2-yl) -2-hydroxye-thane-1-sulfonamide; 2- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-pyrazol-3-yl) pyridin-2-yl) -2-hydroxypro-pane-1-sulfonamide; 3, 3, 3-trifluoro-2- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-pyrazol-3-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; 2-hydroxy-2- (6- (2- (3- (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) propane-1-sul-fonamide; 2- (3-chloro-6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hy-droxypropane-1-sulfonamide; 2- (3-fluoro-6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hy-droxypropane-1-sulfonamide; 2- (6- (2- (5-cyclopropoxy-2-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; 2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxye-thane-1-sulfonamide; 1- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -1-hydroxypro-pane-2-sulfonamide; 1- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-pyrazol-3-yl) pyridin-2-yl) -1-hydroxy-2-methylpropane-2-sulfonamide; 3- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-pyrazol-3-yl) pyridin-2-yl) -3-hydroxy-2-methylbutane-2-sulfonamide; 2- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; 2- (6- (3- (2-fluoro-5- (trifluoromethoxy) benzyl) -1, 2, 4-oxadiazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; 2- (6- (1- (2-fluoro-5- (trifluoromethoxy) benzyl) -1H-1, 2, 3-triazol-4-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; 2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-1, 2, 3-triazol-4-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (2-chloro-6-fluoro-3-methylbenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypro-pane-1-sulfonamide; (R) -2- (6- (2- (2-bromo-5-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2- (6- (2- (4-bromo-2-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2- (6- (2- (3-bromo-2-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2- (6- (2- (2-bromo-6-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2-hydroxy-2- (6- (2- (2, 3, 5-trimethylbenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) propane-1-sul-fonamide; (R) -2- (6- (2- (2, 3-dimethylbenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfon-amide; (R) -2- (6- (2- (2, 3-dichlorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfona-mide; (R) -2- (6- (2- (5-bromo-2-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2-hydroxy-2- (6- (2- (5-isopropyl-2-methylbenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) propane-1-sulfonamide; (R) -2- (6- (2- (3-chloro-2, 6-difluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2- (6- (2- (2-chloro-5- (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (2-fluoro-3- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (2-fluoro-5-methoxybenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2- (6- (2- (2-chloro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (2, 5-dichlorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfona-mide; (R) -2- (6- (2- (2-fluoro-6- (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (4-chloro-3- (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (5-chloro-2, 4-difluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide; (R) -2-hydroxy-2- (6- (2- (3- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) propane-1-sulfonamide; (R) -2- (6- (2- (3, 5-bis (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypro-pane-1-sulfonamide; (R) -2- (6- (2- (5- (difluoromethoxy) -2-fluorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (2, 6-dichlorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfona-mide; (R) -2- (6- (2- (2-bromo-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (2, 3-dichloro-6- (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hy-droxypropane-1-sulfonamide; (R) -2- (6- (2- (3-chloro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; (R) -2- (6- (2- (5-chloro-2- (trifluoromethyl) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide; and (R) -2-hydroxy-2- (6- (2- (2, 3, 5-trichlorobenzyl) -2H-tetrazol-5-yl) pyridin-2-yl) propane-1-sul-fonamide.
  16. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is 2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide,
  17. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: (R) -2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide, and (S) -2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxy-propane-1-sulfonamide,
  18. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is (R) -2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide,
  19. A crystalline form of the compound of claim 18, said crystalline form being a co-crys-tal form named Modification A-1 comprising (R) -2- (6- (2- (2-fluoro-5- (trifluoromethoxy) ben-zyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide and L-proline, wherein the molar ratio of (R) -2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyri-din-2-yl) -2-hydroxypropane-1-sulfonamide to L-proline is about 1: 1, characterized in that said co-crystal form has an X-ray powder diffraction pattern comprising four or more peaks at 2θ angles (± 0.2 degree) selected from 6.8°, 8.0°, 10.2°, 10.6°, 11.3°, 12.1°, 15.4°, 16.1°, 17.2°, 18.0°, 18.7°, 19.1°, 20.2°, 21.4°, 23.9° and 26.0°, when measured using a CuKa radia-tion with a wavelength of at a temperature of about 22 ℃.
  20. A crystalline form of the compound of claim 18, said crystalline form being a co-crystal form named Modification A-2 comprising (R) -2- (6- (2- (2-fluoro-5- (trifluorometh-oxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide and L-proline, wherein the molar ratio of (R) -2- (6- (2- (2-fluoro-5- (trifluoromethoxy) benzyl) -2H-tetrazol-5-yl) pyridin-2-yl) -2-hydroxypropane-1-sulfonamide to L-proline is about 1: 2.9, characterized in that said co-crystal form has an X-ray powder diffraction pattern comprising four or more peaks at 2θ angles (± 0.2 degree) selected from 5.5°, 8.7°, 9.4°, 11.1°, 12.7°, 15.3°, 16.6°, 17.2°, 18.8°, 19.2°, 20.1°, 21.7°, 22.2°, 25.3°, 26.2°, 28.7° and 30.8°, when measured using a CuKa radiation with a wavelength of at a temperature of about 22 ℃.

Description

SODIUM CHANNEL BLOCKERS CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority and benefit to the International Patent Applica-tion PCT/CN2023/106400 filed July 7, 2023, the disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present disclosure relates to sulfonamide compounds, the use thereof for modulat-ing activity of the sodium channel Nav1.5 and methods of treating disease using the same. BACKGROUND Cardiac arrhythmia is an abnormal heart rhythm and occurs when the normal se-quence of electrical impulses in the heart changes. Atrial fibrillation (AF) is one type of ar-rhythmia, and can lead to stroke, heart failure and sudden cardiac death. A normal cardiac cycle begins in the sino-atrial node, which produces an excitatory electrical stimulus that propagates in an orderly fashion throughout the atrial and ventricular myocardium to induce a contraction (systole) . At the cellular level, the excitatory electrical impulse triggers the cardiac action potential. This is characterized by an initial, rapid mem-brane depolarization followed by a plateau phase and subsequent repolarization to return to resting membrane potential. The cardiac action potential governs signal propagation through-out the heart. For example, the rate of initial cellular depolarization determines the velocity at which excitatory stimuli propagate. The duration of the repolarization phase determines the action potential duration (APD) and the effective refractory period (ERP) , or time in which a cardiomyocyte cannot respond to another electrical stimulus. Abnormalities in the cardiac ac-tion potential are associated with arrhythmia. For example, excessive reduction of action po-tential duration and the accompanying, shorter refractory period can provide a substrate for so-called re-entrant tachyarrhythmia. In this condition, instead of propagating normally, a cardiac impulse feeds back upon itself via excitable tissue to form a re-entrant circuit (Waldo and Wit, 1993, Mechanism of cardiac arrhythmias, Lancet 347, 1189-1193) . When a trigger occurs in the atria with a re-entrant substrate, it can cause uncoordinated, fast, and often cha-otic atrial contraction and manifests as atrial fibrillation (AF) . The repetitive or lasting rapid activation can lead to electrical and structural remodeling that further abbreviates atrial  APD/ERP to sustain the duration of AF and worsen the disease prognosis (also called as “AF begets AF” ) (Nattel S., Atrial electrophysiology and mechanisms of atrial fibrillation, Journal of Cardiovascular Pharmacology and Therapeutics, 2003, 8 (Suppl. 1) , S5-S11) . One of the clinical strategies for rhythm control is prolonging the ERP. This approach increases the excitation threshold of atrial tissues and reduces the likelihood of a premature atrial beat, which can render the development or maintenance of AF harder or impossible (Antzelevitch C, Burashnikov A, Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation, Ann N Y Acad Sci., 2010, 1188, 78-86) . Two major rhythm control drug classes exist, termed Class III & I. Dofetilide, sotalol and ibutilide are Class III drugs and primarily target the human ether-a-go-go related gene potassium channels (hERG) involved in cardiac repolarization. hERG blockade prolongs atrial ERP (aERP) against AF by increasing atrial APD. Those drugs also affect ventricular hERG and can cause excessive prolongation of ventricular repolarization –so-called QT prolongation –and pre-dispose to ventricular arrhythmias. Hence, in-hospital initiation of Class III drugs is mandated to mitigate excessive QT prolongation and prevent serious arrhythmia called Torsades de Pointes. Class Ic drugs are primarily sodium channel blockers and can prolong aERP by re-ducing excitability and promoting post-repolarization refractoriness (PRR) against AF. Flecainide, pilsicainide and propafenone belong to this class. Those drugs were originally de-veloped for ventricular arrhythmias and can slow down ventricular conduction significantly via Nav1.5 blockade as manifested as QRS prolongation on the electrocardiogram (ECG) (Antzelevitch C. and Burashnikov A., cited hereinabove) . QRS prolongation or ventricular conduction slowing has been associated with excess of deaths due to arrhythmia in myocar-dial infarction (MI) patients in the Cardiac Arrhythmia Suppression Trial (CAST) (Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial, New England Journal of Medicine, 1991, 324 (12) , 781-788) . As a result, QRS-prolonging Class I drugs are contrain-dicated for AF in the setting of structural heart disease, e.g., MI & heart failure. The cardiac voltage-sensitive sodium channel (Nav1.5) is one of the ion-